Experimental Immunotherapy - ACIR Journal Articles

Immune microenvironment and noncoding RNA shape early colorectal carcinogenesis in patients with premalignant lesions Spotlight

(1) Morgand E (2) Van den Eynde M (3) Nguyen H (4) Batto AF (5) Mlecnik B (6) Baldin P (7) Majdi A (8) Fredriksen T (9) Lafontaine L (10) Bindea G (11) Mezine F (12) Shararah M (13) Vasaturo A (14) Hijazi A (15) Buttard B (16) Maby P (17) Ramos RN (18) Gragera P (19) Kirilovsky A (20) El Sissy C (21) Marliot F (22) Pags F (23) Vempalli FR (24) Hendrickx W (25) Masoodi T (26) Ceccarelli M (27) Bedognetti D (28) Galon J

Science translational medicine

Morgand et al. performed a retrospective, longitudinal study characterizing 258 pre-malignant colorectal lesions across discovery and validation cohorts. Patients were stratified based on polyps per year. Sequenced lesions shared few mutations, suggesting their sporadic and independent origin. Patients with the lowest polyp development rates exhibited lesions characterized by high immune cell infiltration and mature TLSs persisting from initial polyp onset to recurrent lesions. Such lesions showed increased expression of non-coding RNAs, which were associated with higher predicted immunogenicity and increased T cell density in tumor centers.

Contributed by Paula Hochman

(1) Morgand E (2) Van den Eynde M (3) Nguyen H (4) Batto AF (5) Mlecnik B (6) Baldin P (7) Majdi A (8) Fredriksen T (9) Lafontaine L (10) Bindea G (11) Mezine F (12) Shararah M (13) Vasaturo A (14) Hijazi A (15) Buttard B (16) Maby P (17) Ramos RN (18) Gragera P (19) Kirilovsky A (20) El Sissy C (21) Marliot F (22) Pags F (23) Vempalli FR (24) Hendrickx W (25) Masoodi T (26) Ceccarelli M (27) Bedognetti D (28) Galon J

Science translational medicine

Morgand et al. performed a retrospective, longitudinal study characterizing 258 pre-malignant colorectal lesions across discovery and validation cohorts. Patients were stratified based on polyps per year. Sequenced lesions shared few mutations, suggesting their sporadic and independent origin. Patients with the lowest polyp development rates exhibited lesions characterized by high immune cell infiltration and mature TLSs persisting from initial polyp onset to recurrent lesions. Such lesions showed increased expression of non-coding RNAs, which were associated with higher predicted immunogenicity and increased T cell density in tumor centers.

Contributed by Paula Hochman

ABSTRACT: Early cancer detection and prophylactic intervention remain the primary strategies for reducing colorectal carcinoma incidence and mortality. Although the immune microenvironment and tumor-associated antigens have been shown to play a pivotal role in carcinogenesis, the factors shaping immune dynamics during the premalignant phase remain poorly understood. In this study, we performed a comprehensive multimodal characterization of the immune microenvironment in 258 longitudinal premalignant colorectal lesions. Using a discovery cohort of 135 lesions from 26 patients stratified by low versus high polyp development rate, we identified distinct immune states associated with polyp burden. These findings were validated in an independent cohort of 123 lesions from 43 patients. Lesions from patients with low polyp development rates exhibited signatures of robust immune surveillance characterized by enhanced adaptive immune infiltration, including defined T cell subsets, and a higher prevalence of mature tertiary lymphoid structures compared with lesions from patients with high polyp frequency. These immune features were accompanied by increased expression of noncoding RNAs. These transcripts were predicted to encode noncanonical antigens with high MHC-I (major histocompatibility complex class I) binding affinity, potentially increasing lesion immunogenicity. We propose that early carcinogenesis is shaped by the immune microenvironment in association with noncoding RNAs, revealing potential early biomarkers in individuals at high risk of developing colorectal cancer.

Author Info: (1) INSERM, Laboratory of Integrative Cancer Immunology, F-75006 Paris, France. Equipe Labellise Ligue Contre le Cancer, F-75006 Paris, France. Centre de Recherche des Cordeliers,

Author Info: (1) INSERM, Laboratory of Integrative Cancer Immunology, F-75006 Paris, France. Equipe Labellise Ligue Contre le Cancer, F-75006 Paris, France. Centre de Recherche des Cordeliers, Sorbonne Universit, Universit Paris Cit, F-75006 Paris, France. (2) Institut Roi Albert II, Department of Medical Oncology Cliniques Universitaires St-Luc and Institut de Recherche Clinique et Experimentale (Pole MIRO), Universit Catholique de Louvain, 1200 Brussels, Belgium. (3) INSERM, Laboratory of Integrative Cancer Immunology, F-75006 Paris, France. Equipe Labellise Ligue Contre le Cancer, F-75006 Paris, France. Centre de Recherche des Cordeliers, Sorbonne Universit, Universit Paris Cit, F-75006 Paris, France. (4) INSERM, Laboratory of Integrative Cancer Immunology, F-75006 Paris, France. Equipe Labellise Ligue Contre le Cancer, F-75006 Paris, France. Centre de Recherche des Cordeliers, Sorbonne Universit, Universit Paris Cit, F-75006 Paris, France. (5) INSERM, Laboratory of Integrative Cancer Immunology, F-75006 Paris, France. Equipe Labellise Ligue Contre le Cancer, F-75006 Paris, France. Centre de Recherche des Cordeliers, Sorbonne Universit, Universit Paris Cit, F-75006 Paris, France. (6) Department of Pathology, Cliniques Universitaires St-Luc and Institut de Recherche Clinique et Experimentale (Pole GAEN) Universit Catholique de Louvain, 1200 Brussels, Belgium. (7) INSERM, Laboratory of Integrative Cancer Immunology, F-75006 Paris, France. Equipe Labellise Ligue Contre le Cancer, F-75006 Paris, France. Centre de Recherche des Cordeliers, Sorbonne Universit, Universit Paris Cit, F-75006 Paris, France. (8) INSERM, Laboratory of Integrative Cancer Immunology, F-75006 Paris, France. Equipe Labellise Ligue Contre le Cancer, F-75006 Paris, France. Centre de Recherche des Cordeliers, Sorbonne Universit, Universit Paris Cit, F-75006 Paris, France. (9) INSERM, Laboratory of Integrative Cancer Immunology, F-75006 Paris, France. Equipe Labellise Ligue Contre le Cancer, F-75006 Paris, France. Centre de Recherche des Cordeliers, Sorbonne Universit, Universit Paris Cit, F-75006 Paris, France. (10) INSERM, Laboratory of Integrative Cancer Immunology, F-75006 Paris, France. Equipe Labellise Ligue Contre le Cancer, F-75006 Paris, France. Centre de Recherche des Cordeliers, Sorbonne Universit, Universit Paris Cit, F-75006 Paris, France. (11) Universit Paris Cit, INSERM U970 PARCC, Paris Institute for Transplantation and Organ Regeneration, 75015 Paris, France. (12) INSERM, Laboratory of Integrative Cancer Immunology, F-75006 Paris, France. Equipe Labellise Ligue Contre le Cancer, F-75006 Paris, France. Centre de Recherche des Cordeliers, Sorbonne Universit, Universit Paris Cit, F-75006 Paris, France. (13) INSERM, Laboratory of Integrative Cancer Immunology, F-75006 Paris, France. Equipe Labellise Ligue Contre le Cancer, F-75006 Paris, France. Centre de Recherche des Cordeliers, Sorbonne Universit, Universit Paris Cit, F-75006 Paris, France. (14) INSERM, Laboratory of Integrative Cancer Immunology, F-75006 Paris, France. Equipe Labellise Ligue Contre le Cancer, F-75006 Paris, France. Centre de Recherche des Cordeliers, Sorbonne Universit, Universit Paris Cit, F-75006 Paris, France. (15) INSERM, Laboratory of Integrative Cancer Immunology, F-75006 Paris, France. Equipe Labellise Ligue Contre le Cancer, F-75006 Paris, France. Centre de Recherche des Cordeliers, Sorbonne Universit, Universit Paris Cit, F-75006 Paris, France. (16) INSERM, Laboratory of Integrative Cancer Immunology, F-75006 Paris, France. Equipe Labellise Ligue Contre le Cancer, F-75006 Paris, France. Centre de Recherche des Cordeliers, Sorbonne Universit, Universit Paris Cit, F-75006 Paris, France. (17) INSERM, Laboratory of Integrative Cancer Immunology, F-75006 Paris, France. Equipe Labellise Ligue Contre le Cancer, F-75006 Paris, France. Centre de Recherche des Cordeliers, Sorbonne Universit, Universit Paris Cit, F-75006 Paris, France. (18) INSERM, Laboratory of Integrative Cancer Immunology, F-75006 Paris, France. Equipe Labellise Ligue Contre le Cancer, F-75006 Paris, France. Centre de Recherche des Cordeliers, Sorbonne Universit, Universit Paris Cit, F-75006 Paris, France. (19) INSERM, Laboratory of Integrative Cancer Immunology, F-75006 Paris, France. Equipe Labellise Ligue Contre le Cancer, F-75006 Paris, France. Centre de Recherche des Cordeliers, Sorbonne Universit, Universit Paris Cit, F-75006 Paris, France. Assistance Publique-Hpitaux de Paris (AP-HP), Immunomonitoring Platform, Laboratory of Immunology, Georges Pompidou European Hospital, 75015 Paris, France. (20) INSERM, Laboratory of Integrative Cancer Immunology, F-75006 Paris, France. Equipe Labellise Ligue Contre le Cancer, F-75006 Paris, France. Centre de Recherche des Cordeliers, Sorbonne Universit, Universit Paris Cit, F-75006 Paris, France. Assistance Publique-Hpitaux de Paris (AP-HP), Immunomonitoring Platform, Laboratory of Immunology, Georges Pompidou European Hospital, 75015 Paris, France. (21) INSERM, Laboratory of Integrative Cancer Immunology, F-75006 Paris, France. Equipe Labellise Ligue Contre le Cancer, F-75006 Paris, France. Centre de Recherche des Cordeliers, Sorbonne Universit, Universit Paris Cit, F-75006 Paris, France. Assistance Publique-Hpitaux de Paris (AP-HP), Immunomonitoring Platform, Laboratory of Immunology, Georges Pompidou European Hospital, 75015 Paris, France. (22) INSERM, Laboratory of Integrative Cancer Immunology, F-75006 Paris, France. Equipe Labellise Ligue Contre le Cancer, F-75006 Paris, France. Centre de Recherche des Cordeliers, Sorbonne Universit, Universit Paris Cit, F-75006 Paris, France. Assistance Publique-Hpitaux de Paris (AP-HP), Immunomonitoring Platform, Laboratory of Immunology, Georges Pompidou European Hospital, 75015 Paris, France. (23) Sidra Medicine, P.O. Box 26999, Doha, Qatar. (24) Sidra Medicine, P.O. Box 26999, Doha, Qatar. (25) Sidra Medicine, P.O. Box 26999, Doha, Qatar. (26) Sylvester Comprehensive Cancer Center and Department of Public Health Sciences, University of Miami, Miami, FL 33136, USA. (27) Sidra Medicine, P.O. Box 26999, Doha, Qatar. Department of Internal Medicine, University of Genoa, 16132 Genoa, Italy. (28) INSERM, Laboratory of Integrative Cancer Immunology, F-75006 Paris, France. Equipe Labellise Ligue Contre le Cancer, F-75006 Paris, France. Centre de Recherche des Cordeliers, Sorbonne Universit, Universit Paris Cit, F-75006 Paris, France.

Citation: Sci Transl Med 2026 Jun 10 18:eaed2424 Epub06/10/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42268933

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TIGIT-targeted IL-12 fusion protein engages NK and CD8+ T cells for potent tumor immunotherapy
Spotlight

(1) Tang M (2) Huang Y (3) Bi J (4) Meng D (5) Zheng X (6) Peng H (7) Sun R (8) Ma H (9) Tian Z (10) Sun H (11) Zheng X

Cell reports. Medicine - Open Access

To mitigate systemic IL-12 activation, Tang et al. generated T-12, a fusion protein linking IL-12 to an anti-TIGIT scFv that blocks TIGIT binding to its inhibitory receptor. Compared to wild-type IL-12, T-12 selectively localized to tumor sites and activated intratumoral NK and CD8⁺ T cells (both highly expressing TIGIT) to promote NK cell proliferation and reprogram CD8⁺ T cells toward a proliferative, memory-like effector phenotype. T-12 exhibited an MTD ~100X higher than wild-type IL-12, suppressed tumor growth in multiple mouse models (including immunologically “cold”/anti-PD-1 resistant), and reduced metastatic lesions to promote survival by mechanisms requiring both NK and CD8⁺ T cells.

Contributed by Paula Hochman

(1) Tang M (2) Huang Y (3) Bi J (4) Meng D (5) Zheng X (6) Peng H (7) Sun R (8) Ma H (9) Tian Z (10) Sun H (11) Zheng X

Cell reports. Medicine - Open Access

To mitigate systemic IL-12 activation, Tang et al. generated T-12, a fusion protein linking IL-12 to an anti-TIGIT scFv that blocks TIGIT binding to its inhibitory receptor. Compared to wild-type IL-12, T-12 selectively localized to tumor sites and activated intratumoral NK and CD8⁺ T cells (both highly expressing TIGIT) to promote NK cell proliferation and reprogram CD8⁺ T cells toward a proliferative, memory-like effector phenotype. T-12 exhibited an MTD ~100X higher than wild-type IL-12, suppressed tumor growth in multiple mouse models (including immunologically “cold”/anti-PD-1 resistant), and reduced metastatic lesions to promote survival by mechanisms requiring both NK and CD8⁺ T cells.

Contributed by Paula Hochman

ABSTRACT: The limitation of wild-type interleukin-12 (IL-12) in its clinical application lies in its systemic activation, which results in severe toxicities. Here, we develop a fusion protein named _TIGIT-IL12 (T-12), which fuses the 13G6 (_TIGIT) antibody scFv fragment in tandem with IL-12. T-12 can selectively localize to the tumor site and concurrently target intratumoral natural killer (NK) and CD8(+) T cells in vivo. T-12 demonstrated exceptional efficacy in reducing tumor burden across multiple tumor models in mice, dependent on NK and CD8(+) T cells. T-12 preferentially activates tumor-infiltrating NK and CD8(+) T cells over their peripheral counterparts, in contrast to wild-type IL-12. Compared with wild-type IL-12, T-12 exhibits greater safety upon systemic administration while treating tumor-bearing models, and the maximal tolerance dosage was elevated by up to about 100-fold. T-12 exhibits potent therapeutic efficacy in checkpoint-insensitive tumor models and metastatic tumor models. These findings underscore the potential of the T-12 fusion protein as a strategy in immunotherapy.

Author Info: (1) State Key Laboratory of Immune Response and Immunotherapy, Institute of Immunology, School of Basic Medical Sciences, Center for Advanced Interdisciplinary Science and Biomedic

Author Info: (1) State Key Laboratory of Immune Response and Immunotherapy, Institute of Immunology, School of Basic Medical Sciences, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China. (2) CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; Center for Genomic and Personalized Medicine, Guangxi key Laboratory for Genomic and Personalized Medicine, Guangxi Collaborative Innovation Center for Genomic and Personalized Medicine, The First Affiliated Hospital of Guangxi Medical University, Guangxi Medical University, Nanning 530021, Guangxi, China. (3) CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China. (4) CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China. (5) State Key Laboratory of Immune Response and Immunotherapy, Institute of Immunology, School of Basic Medical Sciences, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China. (6) State Key Laboratory of Immune Response and Immunotherapy, Institute of Immunology, School of Basic Medical Sciences, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China. (7) State Key Laboratory of Immune Response and Immunotherapy, Institute of Immunology, School of Basic Medical Sciences, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China; Hefei TG ImmunoPharma Corporation Limited, Hefei, China. (8) State Key Laboratory of Immune Response and Immunotherapy, Institute of Immunology, School of Basic Medical Sciences, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China. Electronic address: mahongdi@ustc.edu.cn. (9) State Key Laboratory of Immune Response and Immunotherapy, Institute of Immunology, School of Basic Medical Sciences, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China; CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; Hefei TG ImmunoPharma Corporation Limited, Hefei, China. Electronic address: tzg@ustc.edu.cn. (10) Department of Immunology, School of Basic Medical Sciences, and Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Hefei TG ImmunoPharma Corporation Limited, Hefei, China. Electronic address: haoyusun@ustc.edu.cn. (11) State Key Laboratory of Immune Response and Immunotherapy, Institute of Immunology, School of Basic Medical Sciences, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China; CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; Hefei TG ImmunoPharma Corporation Limited, Hefei, China. Electronic address: ustczxh@ustc.edu.cn.

Citation: Cell Rep Med 2026 Jun 16 102876 Epub06/16/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42302794

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The critical role of the endogenous immune compartment after CAR T cell therapy in recurrent GBM Spotlight

(1) Freeburg NF (2) Chafamo D (3) Konanur Gopikrishna G (4) Murphy RM (5) Peng JJ (6) Parthasarathy S (7) Dumont S (8) Estrada EG (9) Logun MT (10) Sun Y (11) Wang X (12) Grover P (13) Rodriguez JL (14) Zhang DL (15) Park K (16) Fu Y (17) Ben Hamouda N (18) Hernandez-Verdin I (19) Lamrani L (20) Hicks KA (21) Cooper NA (22) Ekwegbara C (23) Bawden EG (24) Waterfall JJ (25) Fuentealba J (26) Alcantara M (27) Seykora JT (28) Prouty SM (29) Barrett D (30) Banerjee E (31) Cox A (32) Assenmacher CA (33) Macia C (34) Yin M (35) Carpenter EL (36) Ming GL (37) Sauts-Fridman C (38) Fridman WH (39) Tartour E (40) Wherry EJ (41) Amigorena S (42) Fraietta JA (43) Nasrallah MP (44) Song H (45) Miller TE (46) Bagley SJ (47) O'Rourke DM (48) Binder ZA (49) Alanio C (50) Silverbush D

Cell - Open Access

Freeburg and Chafamo et al. performed longitudinal single-cell profiling of CSF and tumors from 18 patients with recurrent GBM treated with a single intracerebroventricular dose of bivalent EGFR-IL13Rα2 CAR T cells. CAR T cells peaked at 7 days and showed increased cytotoxicity and exhaustion in CSF. Endogenous cytotoxic NK cells, Tregs, and “scavenger” myeloid cells also increased dose-dependently. Responses correlated with increased CD56^dimCD16⁺ NK cells, while Treg expansion and a high baseline number of immunosuppressive myeloid cells correlated with non-response, emphasizing the endogenous immune system’s role in CAR T cell efficacy.

Contributed by Katherine Turner

(1) Freeburg NF (2) Chafamo D (3) Konanur Gopikrishna G (4) Murphy RM (5) Peng JJ (6) Parthasarathy S (7) Dumont S (8) Estrada EG (9) Logun MT (10) Sun Y (11) Wang X (12) Grover P (13) Rodriguez JL (14) Zhang DL (15) Park K (16) Fu Y (17) Ben Hamouda N (18) Hernandez-Verdin I (19) Lamrani L (20) Hicks KA (21) Cooper NA (22) Ekwegbara C (23) Bawden EG (24) Waterfall JJ (25) Fuentealba J (26) Alcantara M (27) Seykora JT (28) Prouty SM (29) Barrett D (30) Banerjee E (31) Cox A (32) Assenmacher CA (33) Macia C (34) Yin M (35) Carpenter EL (36) Ming GL (37) Sauts-Fridman C (38) Fridman WH (39) Tartour E (40) Wherry EJ (41) Amigorena S (42) Fraietta JA (43) Nasrallah MP (44) Song H (45) Miller TE (46) Bagley SJ (47) O'Rourke DM (48) Binder ZA (49) Alanio C (50) Silverbush D

Cell - Open Access

Freeburg and Chafamo et al. performed longitudinal single-cell profiling of CSF and tumors from 18 patients with recurrent GBM treated with a single intracerebroventricular dose of bivalent EGFR-IL13Rα2 CAR T cells. CAR T cells peaked at 7 days and showed increased cytotoxicity and exhaustion in CSF. Endogenous cytotoxic NK cells, Tregs, and “scavenger” myeloid cells also increased dose-dependently. Responses correlated with increased CD56^dimCD16⁺ NK cells, while Treg expansion and a high baseline number of immunosuppressive myeloid cells correlated with non-response, emphasizing the endogenous immune system’s role in CAR T cell efficacy.

Contributed by Katherine Turner

ABSTRACT: Glioblastoma (GBM) is the most common primary malignant brain tumor in adults, with a median survival of under 15 months and no effective treatment after recurrence. A recent phase 1 trial of intracerebroventricular bivalent chimeric antigen receptor (CAR) T cells in recurrent GBM, registered at ClinicalTrials.gov (NCT05168423), showed promising responses, including tumor reduction and prolonged survival. However, relapse remains common. We performed in-depth profiling of longitudinal cerebrospinal fluid (CSF) and tumor samples from responders and non-responders to characterize immune dynamics following infusion. Our study reveals that, although CAR T cells activate post infusion across all patients, outcomes were defined by divergent remodeling of the endogenous immune landscape. Cytotoxic natural killer cell expansion characterized responders, whereas regulatory T cell expansion and abundant baseline immunosuppressive scavenger myeloid cells characterized non-responders. These findings indicate that host immune cells play a critical role in CAR T cell therapy for GBM, suggesting that combinatorial strategies modulating the endogenous immune compartment could improve next-generation treatments.

Author Info: (1) Cancer Biology Department, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. (2) Cancer Biology Department, Perelman School of Medicin

Author Info: (1) Cancer Biology Department, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. (2) Cancer Biology Department, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. (3) Cancer Biology Department, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. (4) Department of Pathology, Case Western Reserve University School of Medicine and Case Comprehensive Cancer Center, Cleveland, OH, USA. (5) Cancer Biology Department, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. (6) Cancer Biology Department, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. (7) Department of Neurosurgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; GBM Translational Center of Excellence, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Cell and Molecular Biology Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. (8) Department of Pathology, Case Western Reserve University School of Medicine and Case Comprehensive Cancer Center, Cleveland, OH, USA. (9) Department of Neurosurgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; GBM Translational Center of Excellence, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. (10) Neuroscience Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. (11) Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. (12) Department of Neurosurgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; GBM Translational Center of Excellence, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. (13) Department of Neurosurgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; GBM Translational Center of Excellence, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. (14) Department of Neurosurgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. (15) Neuroscience Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. (16) Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA, USA. (17) Universit Paris Cit, INSERM, PARCC, Paris, France; Department of Immunology, APHP, Hpital Europen Georges Pompidou (HEGP)-Hpital Necker, Paris, France. (18) Centre de Recherche des Cordeliers, Sorbonne Universit, INSERM, Universit Paris Cit, 75006 Paris, France. (19) CellAction, Center for Cancer Immunotherapy, INSERM U932, Institut Curie, Saint-Cloud, France. (20) Department of Neurosurgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; GBM Translational Center of Excellence, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. (21) Department of Neurosurgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; GBM Translational Center of Excellence, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. (22) Clinical Immunology Laboratory, Institut Curie, Paris, France. (23) Institut Curie, PSL University, INSERM U932, Immunity and Cancer, 75005 Paris, France. (24) Department of Translational Research, PSL University, Institut Curie, Paris, France; INSERM U1330, PSL University, Institut Curie Research Center, Paris, France. (25) CellAction, Center for Cancer Immunotherapy, INSERM U932, Institut Curie, Saint-Cloud, France. (26) CellAction, Center for Cancer Immunotherapy, INSERM U932, Institut Curie, Saint-Cloud, France; Clinical Hematology Unit, Institut Curie, Saint-Cloud, France. (27) Departments of Dermatology and Pathology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. (28) Department of Dermatology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. (29) Kite, a Gilead Company, Santa Monica, CA, USA. (30) Comparative Pathology Core, Department of Pathobiology, University of Pennsylvania, School of Veterinary Medicine, Philadelphia, PA, USA. (31) Comparative Pathology Core, Department of Pathobiology, University of Pennsylvania, School of Veterinary Medicine, Philadelphia, PA, USA. (32) Comparative Pathology Core, Department of Pathobiology, University of Pennsylvania, School of Veterinary Medicine, Philadelphia, PA, USA. (33) Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Medicine, Division of Hematology and Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. (34) Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Medicine, Division of Hematology and Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. (35) Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Medicine, Division of Hematology and Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. (36) Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Department of Cell and Developmental Biology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA, USA. (37) Centre de Recherche des Cordeliers, Sorbonne Universit, INSERM, Universit Paris Cit, 75006 Paris, France; quipe labellise Ligue Contre le Cancer, Centre de Recherche des Cordeliers, 15 rue de l'cole de mdecine, 75006 Paris, France. (38) Centre de Recherche des Cordeliers, Sorbonne Universit, INSERM, Universit Paris Cit, 75006 Paris, France; quipe labellise Ligue Contre le Cancer, Centre de Recherche des Cordeliers, 15 rue de l'cole de mdecine, 75006 Paris, France. (39) Universit Paris Cit, INSERM, PARCC, Paris, France; Department of Immunology, APHP, Hpital Europen Georges Pompidou (HEGP)-Hpital Necker, Paris, France. (40) Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Institute for Immunology and Immune Health, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. (41) Institut Curie, PSL University, INSERM U932, Immunity and Cancer, 75005 Paris, France. (42) Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Microbiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Parker Institute for Cancer Immunotherapy, University of Pennsylvania, Philadelphia, PA, USA. (43) GBM Translational Center of Excellence, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. (44) Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Department of Neurosurgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; GBM Translational Center of Excellence, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA, USA; Epigenetics Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. (45) Department of Pathology, Case Western Reserve University School of Medicine and Case Comprehensive Cancer Center, Cleveland, OH, USA; Department of Pathology, University Hospitals Cleveland Medical Center, Cleveland, OH, USA. (46) GBM Translational Center of Excellence, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Medicine, Division of Hematology and Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. (47) Department of Neurosurgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; GBM Translational Center of Excellence, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Parker Institute for Cancer Immunotherapy, University of Pennsylvania, Philadelphia, PA, USA. (48) Department of Neurosurgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; GBM Translational Center of Excellence, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: binderz@pennmedicine.upenn.edu. (49) Department of Neurosurgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Universit Paris Cit, INSERM, PARCC, Paris, France; Clinical Laboratory, Hpital Foch, Suresnes, France. Electronic address: c.alanio@hopital-foch.com. (50) Cancer Biology Department, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Neurosurgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: dana.silverbush@pennmedicine.upenn.edu.

Citation: Cell 2026 Jun 15 Epub06/15/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42296961

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Immunoediting restricts clonal neoantigens in primary, treatment-naive human tumors Spotlight

(1) Borden ES (2) Castellano D (3) Kantzos EA (4) Hughes A (5) Leibovit-Reiben Z (6) Stockard A (7) Choudhary A (8) Ma T (9) Li X (10) Mangold AR (11) Gutenkunst RN (12) LaFleur BJ (13) Buetow KH (14) Wilson MA (15) Hastings KT

Immunity

To investigate immunoediting in human tumors, Borden et al. analyzed primary, treatment-naive cSCC tumors, which frequently arise in immunosuppressed patients following solid organ transplant, suggesting immune involvement. Compared to tumors from immunodeficient patients or just poorly infiltrated tumors, tumors from immunocompetent patients with high infiltration showed lower overall and clonal mutation burdens, and a lower frequency of variant alleles with high predicted neoantigen:MHC-I binding affinity. Further, neoantigens that shared features with validated immunogenic neoantigens were decreased in clonal versus subclonal cancer cells.

Contributed by Lauren Hitchings

(1) Borden ES (2) Castellano D (3) Kantzos EA (4) Hughes A (5) Leibovit-Reiben Z (6) Stockard A (7) Choudhary A (8) Ma T (9) Li X (10) Mangold AR (11) Gutenkunst RN (12) LaFleur BJ (13) Buetow KH (14) Wilson MA (15) Hastings KT

Immunity

To investigate immunoediting in human tumors, Borden et al. analyzed primary, treatment-naive cSCC tumors, which frequently arise in immunosuppressed patients following solid organ transplant, suggesting immune involvement. Compared to tumors from immunodeficient patients or just poorly infiltrated tumors, tumors from immunocompetent patients with high infiltration showed lower overall and clonal mutation burdens, and a lower frequency of variant alleles with high predicted neoantigen:MHC-I binding affinity. Further, neoantigens that shared features with validated immunogenic neoantigens were decreased in clonal versus subclonal cancer cells.

Contributed by Lauren Hitchings

ABSTRACT: T cell targeting of cancer cells alters the tumor antigen landscape in preclinical models. Here, we examined the impact of immunoediting on the antigenic landscape of primary, treatment-naive human tumors. Cutaneous squamous cell carcinoma tumors from immunocompetent and immunosuppressed patients revealed consistent tumor mutational signatures; however, high-immune-infiltrate tumors from immunocompetent patients had lower overall mutational burdens and lower clonal mutational burdens compared with low-infiltrate tumors from immunocompetent patients and tumors from immunosuppressed patients. The lower clonal mutational burden in high-immune-infiltrate tumors from immunocompetent patients persisted after accounting for tumor purity and growth rate. Predicted neoantigen: major histocompatibility complex (MHC) class I binding affinity decreased with increasing variant allele frequency, demonstrating restriction of mutations encoding MHC-binding neoantigens. Neoantigens with features shared with validated immunogenic neoantigens were decreased in clonal relative to subclonal cancer cell populations in high-immune-infiltrate tumors from immunocompetent patients. Thus, the immune system restricts cancer cells expressing immunogenic antigens from clonal populations in primary, treatment-naive human tumors.

Author Info: (1) Department of Dermatology, College of Medicine-Phoenix, University of Arizona, Phoenix, AZ 85004, USA; Phoenix Veterans Affairs Health Care System, Phoenix, AZ 85012, USA. (2)

Author Info: (1) Department of Dermatology, College of Medicine-Phoenix, University of Arizona, Phoenix, AZ 85004, USA; Phoenix Veterans Affairs Health Care System, Phoenix, AZ 85012, USA. (2) Department of Molecular and Cellular Biology, University of Arizona, Tucson, AZ 85721, USA. (3) Department of Dermatology, College of Medicine-Phoenix, University of Arizona, Phoenix, AZ 85004, USA. (4) Department of Dermatology, Mayo Clinic Health System, Scottsdale, AZ 85259, USA. (5) Department of Dermatology, Mayo Clinic Health System, Scottsdale, AZ 85259, USA. (6) Department of Dermatology, Mayo Clinic Health System, Scottsdale, AZ 85259, USA. (7) Department of Electrical and Computer Engineering, University of Illinois Urbana-Champaign, Champaign, IL 61801, USA. (8) Department of Dermatology, Mayo Clinic Health System, Scottsdale, AZ 85259, USA. (9) Department of Dermatology, Mayo Clinic Health System, Scottsdale, AZ 85259, USA. (10) Department of Dermatology, Mayo Clinic Health System, Scottsdale, AZ 85259, USA. (11) Department of Molecular and Cellular Biology, University of Arizona, Tucson, AZ 85721, USA. (12) BIO5 Institute, University of Arizona, Tucson, AZ 85719, USA; R. Ken Coit College of Pharmacy, University of Arizona, Tucson, AZ 85724, USA. (13) School of Life Sciences, Arizona State University, Tempe, AZ 85281, USA; Center for Evolution and Medicine, Arizona State University, Tempe, AZ 85281, USA. (14) School of Life Sciences, Arizona State University, Tempe, AZ 85281, USA; Center for Evolution and Medicine, Arizona State University, Tempe, AZ 85281, USA. (15) Department of Dermatology, College of Medicine-Phoenix, University of Arizona, Phoenix, AZ 85004, USA; Phoenix Veterans Affairs Health Care System, Phoenix, AZ 85012, USA; University of Arizona Cancer Center, University of Arizona, Tucson, AZ 85719, USA. Electronic address: khasting@arizona.edu.

Citation: Immunity 2026 Jun 11 Epub06/11/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42276071

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MAGE-A4/MAGE-A8-targeted TCR-based bispecific T cell engager in recurrent and/or refractory solid tumors: a phase 1 trial Spotlight

(1) Wermke M (2) Ochsenreither S (3) Jaeger D (4) Becker H (5) Bleckmann A (6) Bozorgmehr F (7) Chatterjee M (8) Groepper S (9) Haenel M (10) Hecker JS (11) Häring MF (12) Heudobler D (13) Hilf N (14) Hofmann M (15) Hutt M (16) Mayer-Mokler A (17) Missel S (18) Ruh M (19) Schuster H (20) Veremchuk O (21) Kleemiss M (22) Knop S (23) Laban S (24) Sebastian M (25) Spoerl S (26) Britten CM (27) Reinhardt C

Nature medicine

In a phase 1 trial, 61 patients with advanced solid tumors were treated with a TCE comprising (1) a high-affinity TCR binder for a shared MAGE-A4/MAGE-A8 CTA peptide presented on HLA-A*02:01, (2) a humanized, low(er)-affinity anti-TCRαβ/CD3 antibody for T cell binding and activation, and (3) a silenced Fc domain to extend half-life. 12 patients also received pembrolizumab. Median serum half-life was ~15d, an MTD was not reached, and a RP2D was determined. TRAEs were manageable (often CRS, lymphopenia, or neutropenia) and the ORR was 14% in evaluable patients. Pembrolizumab did not significantly affect safety or response rates.

Contributed by Alex Najibi

(1) Wermke M (2) Ochsenreither S (3) Jaeger D (4) Becker H (5) Bleckmann A (6) Bozorgmehr F (7) Chatterjee M (8) Groepper S (9) Haenel M (10) Hecker JS (11) Häring MF (12) Heudobler D (13) Hilf N (14) Hofmann M (15) Hutt M (16) Mayer-Mokler A (17) Missel S (18) Ruh M (19) Schuster H (20) Veremchuk O (21) Kleemiss M (22) Knop S (23) Laban S (24) Sebastian M (25) Spoerl S (26) Britten CM (27) Reinhardt C

Nature medicine

In a phase 1 trial, 61 patients with advanced solid tumors were treated with a TCE comprising (1) a high-affinity TCR binder for a shared MAGE-A4/MAGE-A8 CTA peptide presented on HLA-A*02:01, (2) a humanized, low(er)-affinity anti-TCRαβ/CD3 antibody for T cell binding and activation, and (3) a silenced Fc domain to extend half-life. 12 patients also received pembrolizumab. Median serum half-life was ~15d, an MTD was not reached, and a RP2D was determined. TRAEs were manageable (often CRS, lymphopenia, or neutropenia) and the ORR was 14% in evaluable patients. Pembrolizumab did not significantly affect safety or response rates.

Contributed by Alex Najibi

ABSTRACT:IMA401 is a T cell receptor (TCR)-based next-generation bispecific T cell engaging receptor (TCER) targeting an HLA-A*02:01-presented peptide derived from MAGE-A4/MAGE-A8 with its high-affinity TCR-based domain, incorporating a low-affinity T-cell-recruiting domain and an optimized Fc domain to prolong half-life. In this prespecified interim analysis of a phase 1 first-in-human trial, 61 patients with advanced solid tumors received intravenous IMA401 (0.0066 mg-2.5 mg) with or without pembrolizumab. The primary endpoint was determination of the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of IMA401 monotherapy and in combination with pembrolizumab. Secondary objectives included safety and tolerability, antitumor activity and pharmacokinetics. The MTD was not reached as defined by the clinical trial protocol, and the RP2D was 1-2 mg IMA401 biweekly. Treatment-related adverse events (TRAEs) were well manageable; the most common any-grade TRAEs were cytokine release syndrome (38%, grades 1-2 only), transient lymphopenia (33%) and reversible neutropenia (31%). Five patients experienced dose-limiting toxicity (DLT) events primarily related to neutropenia. No further DLTs occurred in the RP2D range with dexamethasone premedication. One possibly-related death (pneumonia in a patient with rapidly progressing lung metastases) was reported outside RP2D at 2.5 mg IMA401. In the overall efficacy-evaluable population across all dose levels (n = 56), including low starting doses (from 0.0066 mg), the confirmed objective response rate (ORR) was 14% (8/56). In patients receiving IMA401 at the RP2D, an ORR of 20% (8/41) was observed across 15 different indications (post hoc analysis). In the largest subgroup of patients treated at RP2D, namely head and neck cancer, the ORR was 29% (4/14) with a median duration of response of 8.8 months. These findings show that the bispecific TCER platform has a manageable safety profile with mostly transient adverse events and promising antitumor activity at the RP2D of IMA401 with or without pembrolizumab. ClinicalTrials.gov identifier: NCT05359445 .

Author Info: (1) NCT/UCC Early Clinical Trial Unit and Department of Medicine I, Dresden University of Technology, Dresden, Germany. (2) Charit Universittsmedizin Berlin, Berlin, Germany. (3)

Author Info: (1) NCT/UCC Early Clinical Trial Unit and Department of Medicine I, Dresden University of Technology, Dresden, Germany. (2) Charit Universittsmedizin Berlin, Berlin, Germany. (3) National Center for Tumor Diseases, Heidelberg, Germany. (4) Department of Hematology, Oncology, and Stem Cell Transplantation, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, Germany. (5) Department of Medicine A for Hematology, Oncology and Pneumology, University Hospital Muenster, Muenster, Germany. (6) National Center for Tumor Diseases, Heidelberg, Germany. Thoraxklinik Heidelberg gGmbH, University Hospital Heidelberg, Heidelberg, Germany. (7) University Hospital Wrzburg, Comprehensive Cancer Center Mainfranken, Wrzburg, Germany. (8) Marien Hospital Dsseldorf, Dsseldorf, Germany. (9) Department of Internal Medicine III, Klinikum Chemnitz, Chemnitz, Germany. (10) Department of Medicine III, Technical University of Munich (TUM), Klinikum rechts der Isar, School of Medicine and Health, Munich, Germany. TranslaTUM, Center for Translational Cancer Research, Technical University of Munich (TUM), Munich, Germany. (11) University Hospital of Tbingen, Tbingen, Germany. (12) University Hospital Regensburg, Regensburg, Germany. (13) Immatics Biotechnologies GmbH, Tbingen, Germany. (14) Immatics Biotechnologies GmbH, Tbingen, Germany. (15) Immatics Biotechnologies GmbH, Tbingen, Germany. (16) Immatics Biotechnologies GmbH, Tbingen, Germany. (17) Immatics Biotechnologies GmbH, Tbingen, Germany. (18) Immatics Biotechnologies GmbH, Tbingen, Germany. (19) Immatics Biotechnologies GmbH, Tbingen, Germany. (20) Immatics Biotechnologies GmbH, Tbingen, Germany. (21) University Hospital Bonn, Bonn, Germany. (22) Nuremberg General Hospital, Nuremberg, Germany. (23) Department of Otorhinolaryngology and Head & Neck Surgery, Ulm University Medical Center, Ulm, Germany. (24) University Hospital, Goethe University Frankfurt, Frankfurt Cancer Institute, Frankfurt, Germany. (25) University Hospital Erlangen, Erlangen, Germany. (26) Immatics Biotechnologies GmbH, Tbingen, Germany. (27) Immatics Biotechnologies GmbH, Tbingen, Germany. Carsten.Reinhardt@immatics.com.

Citation: Nat Med 2026 May 31 Epub05/31/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42219399

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Cytotoxic CD39+ tumor-associated NK cells respond to NKG2A blockade in lung cancer
Featured

(1) Serger C (2) Rebuffet L (3) Sandholzer MT (4) Rackwitz W (5) Fusi I (6) Herzig P (7) Brggemann A (8) Pawlow CA (9) Chichelnitskiy E (10) Hajnal D (11) Oelgarth N (12) Uzun S (13) Schulthei§ C (14) Zingg A (15) Tundo S (16) Luu TT (17) Hojski A (18) Lardinois D (19) Neubert L (20) Binder M (21) Mertz K (22) Trefny MP (23) Kirchhammer N (24) Natoli M (25) Matter MS (26) Lubli H (27) Falk C (28) Schaeuble K (29) Vivier E (30) Romagnani A (31) Zippelius A

Science immunology

Serger et al. profiled NK cells in NSCLC, and identified two tumor-associated NK cell (taNK; CD103⁺CD49a⁺) populations. These cells were cytotoxic, but showed hallmarks of dysfunction. Trajectory analysis showed a transition from the CD56^bright phenotype through an interferon response and GZMB induction, leading to the expression of genes related to tissue residency, dysfunction, and cytotoxicity. The CD39-expressing subset of taNK cells had the highest tumor killing capacity and responded to anti-NKG2A therapy.

(1) Serger C (2) Rebuffet L (3) Sandholzer MT (4) Rackwitz W (5) Fusi I (6) Herzig P (7) Brggemann A (8) Pawlow CA (9) Chichelnitskiy E (10) Hajnal D (11) Oelgarth N (12) Uzun S (13) Schulthei§ C (14) Zingg A (15) Tundo S (16) Luu TT (17) Hojski A (18) Lardinois D (19) Neubert L (20) Binder M (21) Mertz K (22) Trefny MP (23) Kirchhammer N (24) Natoli M (25) Matter MS (26) Lubli H (27) Falk C (28) Schaeuble K (29) Vivier E (30) Romagnani A (31) Zippelius A

Science immunology

Serger et al. profiled NK cells in NSCLC, and identified two tumor-associated NK cell (taNK; CD103⁺CD49a⁺) populations. These cells were cytotoxic, but showed hallmarks of dysfunction. Trajectory analysis showed a transition from the CD56^bright phenotype through an interferon response and GZMB induction, leading to the expression of genes related to tissue residency, dysfunction, and cytotoxicity. The CD39-expressing subset of taNK cells had the highest tumor killing capacity and responded to anti-NKG2A therapy.

ABSTRACT: Natural killer (NK) cell-targeting immunotherapies are emerging, yet the differentiation and functional states of tumor-infiltrating NK cells remain poorly understood. Using matched single-nucleus RNA and ATAC sequencing of samples from patients with non-small cell lung cancer (NSCLC), we resolved the transcriptional and epigenetic landscape of intratumoral NK cells. We identified two tumor-associated NK (taNK) cell subsets marked by expression of ITGAE (CD103) and ITGA1 (CD49a) that display features of tissue residency and dysfunction while preserving cytotoxic function. Trajectory and regulon analyses revealed an inflammation-driven transition from early granzyme K (GZMK)(+) NK cells toward an ENTPD1(+) (CD39(+)) effector state characterized by interferon-stimulated gene (ISG) programs. Functional profiling established CD39(+) taNK cells as the dominant cytotoxic NK cell population with superior killing capacity that was further potentiated by NKG2A blockade. This study offers mechanistic insights into NK cell differentiation in NSCLC and establishes CD39(+) taNK cells as a targetable effector population for immunotherapy.

Author Info: (1) Department of Biomedicine, University Hospital and University of Basel, Basel, Switzerland. (2) Aix Marseille Universit, CNRS, INSERM, Centre d'Immunologie de Marseille-Luminy

Author Info: (1) Department of Biomedicine, University Hospital and University of Basel, Basel, Switzerland. (2) Aix Marseille Universit, CNRS, INSERM, Centre d'Immunologie de Marseille-Luminy, Marseille, France. (3) Department of Biomedicine, University Hospital and University of Basel, Basel, Switzerland. (4) Institute of Transplant Immunology, Hannover Medical School, Hannover, Germany. (5) Department of Biomedicine, University Hospital and University of Basel, Basel, Switzerland. (6) Department of Biomedicine, University Hospital and University of Basel, Basel, Switzerland. (7) Institute of Transplant Immunology, Hannover Medical School, Hannover, Germany. (8) Institute of Transplant Immunology, Hannover Medical School, Hannover, Germany. (9) Institute of Transplant Immunology, Hannover Medical School, Hannover, Germany. (10) Department of Biomedicine, University Hospital and University of Basel, Basel, Switzerland. (11) Department of Biomedicine, University Hospital and University of Basel, Basel, Switzerland. (12) Institute of Pathology, University Hospital and University of Basel, Basel, Switzerland. (13) Department of Biomedicine, University Hospital and University of Basel, Basel, Switzerland. (14) Department of Biomedicine, University Hospital and University of Basel, Basel, Switzerland. (15) Department of Biomedicine, University Hospital and University of Basel, Basel, Switzerland. Roche Pharma Research and Early Development pRED, Roche Innovation Center, Basel, Switzerland. (16) Department of Biomedicine, University Hospital and University of Basel, Basel, Switzerland. (17) Department of Thoracic Surgery, University Hospital Basel, Basel, Switzerland. (18) Department of Thoracic Surgery, University Hospital Basel, Basel, Switzerland. (19) German Centre for Lung Diseases (DZL), BREATH site, Hannover, Germany. Institute of Pathology, Hannover Medical School, Hannover, Germany. (20) Department of Biomedicine, University Hospital and University of Basel, Basel, Switzerland. Medical Oncology, University Hospital Basel, Basel, Switzerland. (21) Institute of Pathology, University Hospital and University of Basel, Basel, Switzerland. (22) Department of Biomedicine, University Hospital and University of Basel, Basel, Switzerland. (23) Department of Biomedicine, University Hospital and University of Basel, Basel, Switzerland. (24) Department of Biomedicine, University Hospital and University of Basel, Basel, Switzerland. (25) Institute of Pathology, University Hospital and University of Basel, Basel, Switzerland. (26) Department of Biomedicine, University Hospital and University of Basel, Basel, Switzerland. Medical Oncology, University Hospital Basel, Basel, Switzerland. (27) Institute of Transplant Immunology, Hannover Medical School, Hannover, Germany. German Centre for Lung Diseases (DZL), BREATH site, Hannover, Germany. German Centre for Infection Research (DZIF), TTU-IICH, Hannover/Braunschweig site, Hannover, Germany. (28) Department of Biomedicine, University Hospital and University of Basel, Basel, Switzerland. (29) Aix Marseille Universit, CNRS, INSERM, Centre d'Immunologie de Marseille-Luminy, Marseille, France. APHM, Hpital de la Timone, Marseille-Immunople Profiling Platform, Marseille, France. Paris-Saclay Cancer Cluster, Villejuif, France. Ecole Polytechnique, Palaiseau, France. (30) Roche Pharma Research and Early Development pRED, Roche Innovation Center, Basel, Switzerland. (31) Department of Biomedicine, University Hospital and University of Basel, Basel, Switzerland. Medical Oncology, University Hospital Basel, Basel, Switzerland.

Citation: Sci Immunol 2026 Jun 5 11:eaeb6645 Epub06/05/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42247486

Tags:

Tumor transcriptional state predicts survival in immune-checkpoint-blockade-treated glioblastoma Spotlight

(1) Ghannam JY (2) Bryan J (3) Weiss J (4) Kovarsky D (5) Merrell D (6) Messer C (7) Schlueter-Kuck K (8) Fell GG (9) Lim-Fat MJ (10) Youssef G (11) Rahman R (12) Qin L (13) Young GS (14) Janes JT 3rd (15) Van Orden M (16) Pfaff KL (17) Gans A (18) Lin ES (19) Huang RY (20) Danysh BP (21) Parida L (22) Li S (23) Wen PY (24) Chiocca EA (25) Neuberg D (26) Ligon KL (27) Tirosh I (28) Reardon DA (29) Getz G (30) Wu CJ

Nature cancer

Using bulk DNA/RNA sequencing and single-nucleus RNAseq, Ghannam et al. profiled 181 ICB-treated glioblastomas, benchmarking against standard-of-care cohorts, to define genomic correlates of ICB response. At baseline, an mesenchymal (MES) transcriptional subtype with high HLA class I expression and increased T cell infiltration was predictive of improved survival after ICB, but not chemoradiation, whereas non-MES-linked lesions were associated with worse ICB outcomes. TMB was not predictive of outcomes, and a longitudinal analysis showed ICB selected for subclones with non-MES features as a trajectory of acquired ICB resistance in GBM.

Contributed by Shishir Pant

(1) Ghannam JY (2) Bryan J (3) Weiss J (4) Kovarsky D (5) Merrell D (6) Messer C (7) Schlueter-Kuck K (8) Fell GG (9) Lim-Fat MJ (10) Youssef G (11) Rahman R (12) Qin L (13) Young GS (14) Janes JT 3rd (15) Van Orden M (16) Pfaff KL (17) Gans A (18) Lin ES (19) Huang RY (20) Danysh BP (21) Parida L (22) Li S (23) Wen PY (24) Chiocca EA (25) Neuberg D (26) Ligon KL (27) Tirosh I (28) Reardon DA (29) Getz G (30) Wu CJ

Nature cancer

Using bulk DNA/RNA sequencing and single-nucleus RNAseq, Ghannam et al. profiled 181 ICB-treated glioblastomas, benchmarking against standard-of-care cohorts, to define genomic correlates of ICB response. At baseline, an mesenchymal (MES) transcriptional subtype with high HLA class I expression and increased T cell infiltration was predictive of improved survival after ICB, but not chemoradiation, whereas non-MES-linked lesions were associated with worse ICB outcomes. TMB was not predictive of outcomes, and a longitudinal analysis showed ICB selected for subclones with non-MES features as a trajectory of acquired ICB resistance in GBM.

Contributed by Shishir Pant

ABSTRACT: The determinants of immune checkpoint blockade (ICB) response in glioblastoma (GBM) with wild-type isocitrate dehydrogenase remain poorly understood. Here we profiled 181 ICB-treated GBM cases using bulk DNA sequencing, bulk RNA sequencing and single-nucleus RNA sequencing to investigate the genomic features associated with ICB outcomes. Baseline tumor transcriptional subtype was predictive of overall survival following ICB, with mesenchymal (MES) GBM associated with improved outcomes to ICB but not standard chemoradiation. Non-MES-associated genetic lesions, including those in PDGFRA and CDKN2A, were associated with worse survival following ICB but not standard therapy. Tumor mutational burden was not predictive of outcomes. Survival was associated with pre-ICB enrichment for MES-like malignant cells, marked by high human leukocyte antigen class I expression and greater T cell infiltration. Paired tumor analyses linked ICB exposure to outgrowth of subclones harboring lesions associated with non-MES subtypes, supporting MES-to-non-MES transition as a common trajectory of acquired resistance to ICB, distinct from standard chemoradiation.

Author Info: (1) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Author Info: (1) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. Harvard/MIT MD-PhD Program and Harvard Immunology PhD Program, Harvard Medical School, Boston, MA, USA. (2) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. Molecular Diagnostics Laboratory, Division of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (3) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (4) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel. (5) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (6) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (7) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (8) Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, USA. (9) Division of Neurology, Department of Medicine, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada. (10) Harvard Medical School, Boston, MA, USA. Center for Neuro-Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (11) Department of Radiation Oncology, Brigham and Women's Hospital, Boston, MA, USA. (12) Department of Imaging, Dana-Farber Cancer Institute, and Harvard Medical School, Boston, MA, USA. (13) Departments of Radiology, Mass General Brigham, Brigham and Women's Hospital, Dana-Farber Cancer Institute, and Harvard Medical School, Boston, MA, USA. (14) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, MA, USA. (15) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, MA, USA. (16) Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (17) Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (18) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (19) Departments of Radiology, Mass General Brigham, Brigham and Women's Hospital, Dana-Farber Cancer Institute, and Harvard Medical School, Boston, MA, USA. (20) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (21) IBM Research, Yorktown Heights, NY, USA. (22) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, MA, USA. (23) Center for Neuro-Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (24) Center for Tumors of the Nervous System, Mass General Brigham Cancer Institute & Department of Neurosurgery, Mass General Brigham, Boston, MA, USA. (25) Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, USA. (26) Broad Institute of MIT and Harvard, Cambridge, MA, USA. Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. Department of Pathology, Dana-Farber Cancer Institute, Boston, MA, USA. (27) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel. (28) Center for Neuro-Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (29) Harvard Medical School, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. Cancer Center and Department of Pathology, Massachusetts General Hospital, Boston, MA, USA. (30) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. catherine_wu@dfci.harvard.edu. Harvard Medical School, Boston, MA, USA. catherine_wu@dfci.harvard.edu. Broad Institute of MIT and Harvard, Cambridge, MA, USA. catherine_wu@dfci.harvard.edu.

Citation: Nat Cancer 2026 Jun 3 Epub06/03/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42237038

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FAP-CD40 and PD1-IL2v combination therapy reprograms immunologically cold tumors through de novo intratumoral T cell-dendritic cell clusters Spotlight

(1) Nguyen TT (2) Gómez H (3) Lutge M (4) Yángüez E (5) Hüsser T (6) Nassiri S (7) Trumpfheller C (8) Colombetti S (9) Codarri Deak L (10) Umaña P (11) Tugues S (12) Grazina de Matos I (13) Kunz L

Journal for immunotherapy of cancer - Open Access | Free PMC Article

In a KPC tumor model, Nguyen et al. combined a FAP-targeted CD40 agonist (FAP-CD40; localizes CD40 stimulation to the TME) and PD1–IL-2v (targets a mutated IL-2 to PD-1⁺ T cells and not Tregs). FAP-CD40 alone activated TME cDC1s, which migrated to tdLNs. Combination therapy expanded TME T cells and increased CD4⁺/CD8⁺/cDC1 clustering and therapeutic efficacy (dependent on both CD4⁺ and CD8⁺ T cells) compared to monotherapies. FTY720 blockade of LN egress did not preclude clustering or efficacy, suggesting activation of TME T cells. Combination therapy boosted TME T cell Th1 gene expression, TNFα/IFNγ production, and Nur77 promoter activity.

Contributed by Alex Najibi

(1) Nguyen TT (2) Gómez H (3) Lutge M (4) Yángüez E (5) Hüsser T (6) Nassiri S (7) Trumpfheller C (8) Colombetti S (9) Codarri Deak L (10) Umaña P (11) Tugues S (12) Grazina de Matos I (13) Kunz L

Journal for immunotherapy of cancer - Open Access | Free PMC Article

In a KPC tumor model, Nguyen et al. combined a FAP-targeted CD40 agonist (FAP-CD40; localizes CD40 stimulation to the TME) and PD1–IL-2v (targets a mutated IL-2 to PD-1⁺ T cells and not Tregs). FAP-CD40 alone activated TME cDC1s, which migrated to tdLNs. Combination therapy expanded TME T cells and increased CD4⁺/CD8⁺/cDC1 clustering and therapeutic efficacy (dependent on both CD4⁺ and CD8⁺ T cells) compared to monotherapies. FTY720 blockade of LN egress did not preclude clustering or efficacy, suggesting activation of TME T cells. Combination therapy boosted TME T cell Th1 gene expression, TNFα/IFNγ production, and Nur77 promoter activity.

Contributed by Alex Najibi

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) remains a major challenge for immunotherapy due to its immunologically cold tumor nature, characterized by poor T cell infiltration and a highly suppressive tumor microenvironment. Here, we propose a novel strategy, combining fibroblast activation protein (FAP)-CD40 to activate dendritic cells (DCs) in the tumor microenvironment and programmed cell death protein-1 (PD1)-interleukin 2v (IL2v) to promote the expansion and differentiation of tumor-infiltrating T cells. We hypothesize that this combination will synergistically enhance both T cell priming and expansion directly within pancreatic 4662 KPC tumors, which recapitulate the immunologically cold features of human PDAC. METHODS: Immune cell distribution and abundance following FAP-CD40/PD1-IL2v monotherapy or combination therapy were analyzed using multiplexed confocal imaging (3D immune phenotyping). FTY720 studies assessed the contribution of lymph node priming in treatment efficacy, while CD4+/CD8+ T cell depletion experiments identified the roles of these subsets in combination therapy. T cell functionality was further assessed through ex vivo restimulation assays and single-cell RNA sequencing. RESULTS: Combination therapy induced dense intratumoral clusters of CD4(+) and CD8(+) T cells, colocalized with type 1 conventional DCs, termed as T cell-DC clusters (TDCs). These TDCs were strongly associated with tumor regression, which required both CD4(+) and CD8(+) T cells. Furthermore, T cells from combination-treated tumors showed enhanced functionality, with increased tumor necrosis factor-alpha and interferon-gamma production compared with monotherapy groups. Single-cell RNA sequencing revealed polarization of CD4(+) T cells toward a T helper cell 1 phenotype in combination-treated tumors. CONCLUSION: The combination of FAP-CD40 and PD1-IL2v offers a promising strategy for treating poorly infiltrated, cold tumors. By driving T cell infiltration, promoting de novo TDC formation and orchestrating local antitumor immunity, this strategy provides a foundation for future therapies targeting immunotherapy-resistant tumors.

Author Info: (1) Roche Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland. (2) Roche Pharma Research and Early Development, Roche Innovation Center Ba

Author Info: (1) Roche Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland. (2) Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland. (3) Roche Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland. (4) Roche Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland. (5) Roche Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland. (6) Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland. (7) Roche Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland. (8) Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland. (9) Roche Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland. (10) Roche Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland. (11) Institute of Experimental Immunology, Universitt Zrich, Zrich, Switzerland. Department of Immunology, Heidelberg University Medical Faculty Mannheim, Mannheim, Germany. (12) Roche Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland. (13) Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland leo.kunz@roche.com.

Citation: J Immunother Cancer 2026 May 28 14: Epub05/28/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42208978

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Targeting CCR1 remodels the tumor microenvironment and relieves immune suppression in pancreatic cancer Featured

(1) Zhang Y (2) Kadiyala P (3) Yan W (4) Brown K (5) Avritt FR (6) Donahue KL (7) Procario MC (8) Okoye JO (9) Giridharan T (10) Elhossiny AM (11) Espinoza CE (12) Awad D (13) Lasse Opsahl EL (14) Medina-Cabrera PI (15) Velez-Delgado A (16) Menjivar RE (17) Yang OA (18) Yang S (19) He X (20) Gupta S (21) Tariq R (22) Brandt AR (23) Wang X (24) denDekker A (25) Nwosu ZC (26) Carpenter ES (27) Courtney AH (28) Bednar F (29) Frankel TL (30) Lyssiotis CA (31) Zheng B (32) Kryczek I (33) Pasca di Magliano M

Cancer immunology research

Evaluating the role of CCR1 in pancreatic cancer, Zhang et al. used KC and KPC mouse tumor models, and found while elimination of CCR1 did not limit tumor formation, it delayed progression of active disease, resulting in prolonged survival. CCR1 was mainly expressed by macrophages and granulocytes, but its deletion induced TIME remodeling that affected fibroblasts and increased CD8⁺ T cell accumulation, but not activation. CCR1 inhibition showed synergy in combination with targeting of other immunosuppressive mechanisms, though there was still room to improve antitumor efficacy in this highly resistant tumor setting.

(1) Zhang Y (2) Kadiyala P (3) Yan W (4) Brown K (5) Avritt FR (6) Donahue KL (7) Procario MC (8) Okoye JO (9) Giridharan T (10) Elhossiny AM (11) Espinoza CE (12) Awad D (13) Lasse Opsahl EL (14) Medina-Cabrera PI (15) Velez-Delgado A (16) Menjivar RE (17) Yang OA (18) Yang S (19) He X (20) Gupta S (21) Tariq R (22) Brandt AR (23) Wang X (24) denDekker A (25) Nwosu ZC (26) Carpenter ES (27) Courtney AH (28) Bednar F (29) Frankel TL (30) Lyssiotis CA (31) Zheng B (32) Kryczek I (33) Pasca di Magliano M

Cancer immunology research

Evaluating the role of CCR1 in pancreatic cancer, Zhang et al. used KC and KPC mouse tumor models, and found while elimination of CCR1 did not limit tumor formation, it delayed progression of active disease, resulting in prolonged survival. CCR1 was mainly expressed by macrophages and granulocytes, but its deletion induced TIME remodeling that affected fibroblasts and increased CD8⁺ T cell accumulation, but not activation. CCR1 inhibition showed synergy in combination with targeting of other immunosuppressive mechanisms, though there was still room to improve antitumor efficacy in this highly resistant tumor setting.

ABSTRACT: A hallmark of pancreatic cancer is an extensive fibroinflammatory stroma. Myeloid cells, including abundant macrophages, are a prevalent cellular component of the pancreatic cancer microenvironment and a key driver of immunosuppression. Identifying mechanisms of myeloid-cell driven immunosuppression is thus key to developing therapeutic approaches. Harnessing single-cell RNA sequencing data from human and murine tumors, we determined that tumor infiltrating myeloid cells (including macrophages and granulocytes) have elevated expression of C-C motif chemokine receptor 1 (CCR1). To determine the functional role of CCR1, we generated oncogenic KRAS based genetically engineered mouse models of pancreatic cancer, with or without addition of a mutant form of the tumor suppressor Trp53 (KC and KPC, respectively), lacking CCR1 expression. CCR1 inactivation did not affect formation of early lesions, but delayed progression to cancer and resulted in prolonged survival. In these mice, macrophages lacking CCR1 had reduced expression of the immunosuppressive marker Arginase 1. Loss of CCR1 also profoundly shifted the prevalent fibroblast population, inducing a pancreatic stellate cell-like phenotype. In two independent syngeneic orthotopic models, ablation or pharmacologic inhibition of CCR1 reduced tumor growth and increased CD8+ T cell cytotoxic activity, sensitizing tumors to immunotherapy. Our data show that CCR1-expressing myeloid cells promote pancreatic cancer growth through modulation of the immune microenvironment and fibroblasts, indicating that CCR1 might be a suitable target for combination therapy.

Author Info: (1) University of Michigan-Ann Arbor Ann Arbor, MI United States. ROR: https://ror.org/00jmfr291 (2) University of Michigan-Ann Arbor Ann Arbor, MI United States. (3) University of

Author Info: (1) University of Michigan-Ann Arbor Ann Arbor, MI United States. ROR: https://ror.org/00jmfr291 (2) University of Michigan-Ann Arbor Ann Arbor, MI United States. (3) University of Michigan-Ann Arbor Ann Arbor, Michigan United States. ROR: https://ror.org/00jmfr291 (4) University of Michigan Medical Schooligan United States. (5) University of Michigan-Ann Arbor Ann Arbor, Michigan United States. ROR: https://ror.org/00jmfr291 (6) University of Michigan-Ann Arbor Ann Arbor, Michigan United States. ROR: https://ror.org/00jmfr291 (7) University of Michigan-Ann Arbor Ann Arbor, MI United States. ROR: https://ror.org/00jmfr291 (8) University of Michigan-Ann Arbor Ann Arbor, MI United States. ROR: https://ror.org/00jmfr291 (9) University of Michigan-Ann Arbor Ann Arbor, MI United States. ROR: https://ror.org/00jmfr291 (10) University of Michigan-Ann Arbor Ann Arbor, MI United States. ROR: https://ror.org/00jmfr291 (11) University of Michigan-Ann Arbor Ann Arbor United States. ROR: https://ror.org/00jmfr291 (12) University of Michigan-Ann Arbor United States. ROR: https://ror.org/00jmfr291 (13) University of Maryland, Baltimore Baltimore United States. ROR: https://ror.org/04rq5mt64 (14) University of Michigan-Ann Arbor Ann Arbor, Michigan United States. ROR: https://ror.org/00jmfr291 (15) University of Michigan-Ann Arbor Ann Arbor United States. ROR: https://ror.org/00jmfr291 (16) University of Michigan-Ann Arbor United States. ROR: https://ror.org/00jmfr291 (17) University of Michigan-Ann Arbor United States. ROR: https://ror.org/00jmfr291 (18) University of Michigan-Ann Arbor Ann Arbor, Michigan United States. ROR: https://ror.org/00jmfr291 (19) University of Michigan-Ann Arbor United States. ROR: https://ror.org/00jmfr291 (20) University of Michigan-Ann Arbor Ann Arbor, Michigan United States. ROR: https://ror.org/00jmfr291 (21) University of Michigan-Ann Arbor Ann Arbor, Michigan United States. ROR: https://ror.org/00jmfr291 (22) University of Michigan-Ann Arbor Ann Arbor, Michigan United States. ROR: https://ror.org/00jmfr291 (23) University of Michigan-Ann Arbor Ann Arbor United States. ROR: https://ror.org/00jmfr291 (24) University of Michigan-Ann Arbor United States. ROR: https://ror.org/00jmfr291 (25) Cornell University Ithaca United States. ROR: https://ror.org/05bnh6r87 (26) University of Michigan-Ann Arbor Ann Arbor, MI United States. ROR: https://ror.org/00jmfr291 (27) University of Michigan-Ann Arbor Ann Arbor, MI United States. ROR: https://ror.org/00jmfr291 (28) University of Michigan-Ann Arbor Ann Arbor, Michigan United States. ROR: https://ror.org/00jmfr291 (29) University of Michigan-Ann Arbor Ann Arbor, MI United States. ROR: https://ror.org/00jmfr291 (30) University of Michigan-Ann Arbor Ann Arbor, MI United States. ROR: https://ror.org/00jmfr291 (31) Cedars-Sinai Medical Center Los Angeles, CA United States. ROR: https://ror.org/02pammg90 (32) University of Michigan-Ann Arbor Ann Arbor, MI United States. ROR: https://ror.org/00jmfr291 (33) University of Michigan-Ann Arbor Ann Arbor, MI United States. ROR: https://ror.org/00jmfr291

Citation: Cancer Immunol Res 2026 May 28 Epub05/28/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42207977

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Pembrolizumab plus high-dose IL-2 in advanced clear cell renal cell carcinoma: six-year survival outcomes and molecular signatures from a phase 2 trial Spotlight

(1) Johnson JS (2) Miller JW (3) Hatoum F (4) Schell MJ (5) Yu X (6) Roman Souza G (7) Mizelle S (8) Gullapalli K (9) Fazili A (10) Jain R (11) Chatzkel J (12) Cen L (13) Dhillon J (14) Cubitt C (15) Yao J (16) Whiting J (17) Li J (18) Swank J (19) Jameel G (20) Zhang J (21) Wang X (22) Spiess PE (23) Fishman M (24) Chahoud J

Nature communications - Open Access

In a phase 2 clinical trial of a short-course regimen (median 7 months) of pembrolizumab (anti-PD-1) plus high-dose IL-2 in patients with advanced ccRCC, Johnson et al. reported that at a median follow-up of over 6 years, the ORR was 73%, with 42% CRs and a 92% DCR. Median OS was over 84 months, and median PFS was 19.3 months. Patients were able to remain off treatment for a median of 23.8 months, with 42% of patients off treatment at 5 years. Potential biomarkers for durable clinical benefit included elevated CD16⁺ NK cells, enhanced innate immunity, reduced PD-1⁺ T cells, and patterns of IL-2-induced immune remodeling.

Contributed by Lauren Hitchings

(1) Johnson JS (2) Miller JW (3) Hatoum F (4) Schell MJ (5) Yu X (6) Roman Souza G (7) Mizelle S (8) Gullapalli K (9) Fazili A (10) Jain R (11) Chatzkel J (12) Cen L (13) Dhillon J (14) Cubitt C (15) Yao J (16) Whiting J (17) Li J (18) Swank J (19) Jameel G (20) Zhang J (21) Wang X (22) Spiess PE (23) Fishman M (24) Chahoud J

Nature communications - Open Access

In a phase 2 clinical trial of a short-course regimen (median 7 months) of pembrolizumab (anti-PD-1) plus high-dose IL-2 in patients with advanced ccRCC, Johnson et al. reported that at a median follow-up of over 6 years, the ORR was 73%, with 42% CRs and a 92% DCR. Median OS was over 84 months, and median PFS was 19.3 months. Patients were able to remain off treatment for a median of 23.8 months, with 42% of patients off treatment at 5 years. Potential biomarkers for durable clinical benefit included elevated CD16⁺ NK cells, enhanced innate immunity, reduced PD-1⁺ T cells, and patterns of IL-2-induced immune remodeling.

Contributed by Lauren Hitchings

ABSTRACT: Prolonged or indefinite systemic therapy remains standard for advanced clear cell renal cell carcinoma (ccRCC), often resulting in cumulative toxicities and treatment burden. We conducted a single-arm phase 2 trial (ClinicalTrials.gov identifier: NCT02964078) of a fixed-duration regimen of anti-PD1 pembrolizumab plus high-dose interleukin-2 in treatment-naive advanced ccRCC. Primary objectives of safety and response were previously reported. The study met its primary endpoint with an overall response rate exceeding the pre-specified threshold of 45%. Here we report long-term follow-up (median follow-up of 76.4 months) including overall response, progression-free survival, treatment-free interval, and correlative analysis. Among 26 patients treated, the objective response rate was 73%, with complete responses in 42% of patients. Median overall survival was >84 months with a 5-year restricted mean survival time of 48.6 months. Median progression-free survival was 19.3 months, and median treatment-free interval was 23.8 months. 42% of patients remained treatment-free at the 5-year timepoint. No grade 5 adverse events occurred, and no patients with durable disease control experienced persistent grade ≥2 toxicities. Correlative analyses identified exploratory immune patterns associated with durable benefit, including enrichment of CD16⁺ natural killer cells, suppression of PD-1⁺ T-cell frequencies, and coordinated chemokine, complement, and PKC/TGF-β pathway activation.

Author Info: (1) Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA. (2) USF Health Morsani College of Medicine, Tampa, FL, USA. (3) Department of Genitourinary

Author Info: (1) Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA. (2) USF Health Morsani College of Medicine, Tampa, FL, USA. (3) Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA. (4) Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center, Tampa, FL, USA. (5) Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center, Tampa, FL, USA. (6) Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA. (7) Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA. (8) Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA. (9) Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA. (10) Department of Genitourinary Oncology, Weill Cornell Medicine, New York, NY, USA. (11) Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA. (12) Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center, Tampa, FL, USA. (13) Department of Anatomic Pathology, H. Lee Moffitt Cancer Center, Tampa, FL, USA. (14) Immune Monitoring Core, H. Lee Moffitt Cancer Center, Tampa, FL, USA. (15) Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center, Tampa, FL, USA. (16) Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center, Tampa, FL, USA. (17) Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center, Tampa, FL, USA. (18) Department of Pharmacy, H. Lee Moffitt Cancer Center, Tampa, FL, USA. (19) Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA. (20) Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA. (21) Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center, Tampa, FL, USA. (22) Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA. (23) USF Health Morsani College of Medicine, Tampa, FL, USA. Tampa General Hospital Cancer Institute, Tampa, FL, USA. (24) Department of Genitourinary Oncology, Orlando Health Cancer Institute, Orlando, FL, USA. Jad.Chahoud@orlandohealth.com.

Citation: Nat Commun 2026 May 25 Epub05/25/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42185255

Immune microenvironment and noncoding RNA shape early colorectal carcinogenesis in patients with premalignant lesions Spotlight

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TIGIT-targeted IL-12 fusion protein engages NK and CD8+ T cells for potent tumor immunotherapy Spotlight

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The critical role of the endogenous immune compartment after CAR T cell therapy in recurrent GBM Spotlight

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Immunoediting restricts clonal neoantigens in primary, treatment-naive human tumors Spotlight

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MAGE-A4/MAGE-A8-targeted TCR-based bispecific T cell engager in recurrent and/or refractory solid tumors: a phase 1 trial Spotlight

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Cytotoxic CD39+ tumor-associated NK cells respond to NKG2A blockade in lung cancer Featured

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Tumor transcriptional state predicts survival in immune-checkpoint-blockade-treated glioblastoma Spotlight

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FAP-CD40 and PD1-IL2v combination therapy reprograms immunologically cold tumors through de novo intratumoral T cell-dendritic cell clusters Spotlight

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Targeting CCR1 remodels the tumor microenvironment and relieves immune suppression in pancreatic cancer Featured

Tags:

Pembrolizumab plus high-dose IL-2 in advanced clear cell renal cell carcinoma: six-year survival outcomes and molecular signatures from a phase 2 trial Spotlight

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TIGIT-targeted IL-12 fusion protein engages NK and CD8+ T cells for potent tumor immunotherapy
Spotlight

Cytotoxic CD39+ tumor-associated NK cells respond to NKG2A blockade in lung cancer
Featured