ACIR Journal Articles

Subclinical cholestasis is a hallmark of gut dysbiosis causing resistance to cancer immunotherapy

Anne-Laure Mallard de La Varende (1); Ai-Ling Tian,1 Simon Thomas (1); Imran Lahmar (1); Meriem Messaoudene (2); Sijing Li (3); Omar Motiño (3,4); Hortense Guillaume-dit-Taunière (1); Valerio Iebba (1); Yoan Hurtado (1); Thao-Nguyen Pham (1); Cassandra Thélémaque (1); Miguel Araujo-Voces (1); Deborah Suissa (1); Pierre Ly (1); Ella Reich (1); Giacomo Vitali (5); Bryan Thierry Arlunno (1); Sylvere Durand (6); Fanny Aprahamian (6); Marion Leduc (3,6); Sabrina Forveille (3,6); Oliver Kepp (3,6); Carlos de la Calle-Fabregat (7); Angela Schippers (8); Norbert Wagner (8); Pierre-Edouard Fournier (9); Kenya Honda (10,11,12); Federica Marmorino (13); Chiara Cremolini (13,14); Saman Maleki Vareki (15,16,17,18).

Cancer Cell - Open Access

ABSTRACT: Gut dysbiosis compromises cancer immunosurveillance by downregulating ileal mucosal addressin cell adhesion molecule 1 (MAdCAM-1), but the metabolic landscape associated with gut dysbiosis remains elusive. Here, we show that antibiotics (ABX) or ABX-associated Enterocloster species lead to the loss of secondary bile acids (BAs) including deoxycholic acid (DCA) and the accumulation of tauro-conjugated primary BAs (tauro-chenodeoxycholic acid [TCDCA] and tauro-β-muricholic acid [T-βMCA]) from the alternative pathway in the plasma of patients and mice. Fecal microbial transplantation (FMT), the ileum-specific farnesoid X receptor (FXR) agonist fexaramine, or glycodeoxycholic acid (GDCA) compen- sated dysbiosis-associated BA abnormalities and circumvent primary resistance to PD-1 blockade. GDCA curtailed ABX-induced MAdCAM-1 downregulation and T cell exhaustion in tumors. Subclinical cholestasis defined by elevation of γ-glutamyl transferase (γGT) correlated with increased TCDCA and decreased sMAdCAM-1 in plasma and predicted poor survival in multivariate analyses in six cohorts of patients who received immunotherapy. Hence, subclinical cholestasis accompanies gut dysbiosis, paving the way to immunoresistance.

Author Info: 1- Université Paris-Saclay, Gustave Roussy (GRCC), ClinicObiome, Inserm UMR1367, Microbiota and Mucosal Immunity for Cancer Immunotherapy, 94805 Villejuif, France. 2- Centre de rec

Author Info: 1- Université Paris-Saclay, Gustave Roussy (GRCC), ClinicObiome, Inserm UMR1367, Microbiota and Mucosal Immunity for Cancer Immunotherapy, 94805 Villejuif, France. 2- Centre de recherche Du CHUM (CRCHUM), Montréal, QC H2W1T8, Canada. 3- Centre de Recherche des Cordeliers, INSERM U1138, Equipe Labellisée – Ligue Nationale Contre le Cancer, Université Paris Cité, Sorbonne Université, 75006 Paris, France. 4- Unidad de Excelencia, Instituto de Biomedicina y Genética Molecular de Valladolid, Consejo Superior de Investigaciones Científicas-Universidad de Valladolid, 47001 Valladolid, Spain. 5- MetaGenoPolis, INRAe, Université Paris-Saclay 78350 Jouy en Josas, France. 6- Université Paris-Saclay, INSERM US23, Analyse moléculaire, modélisation et imagerie de la maladie Cancéreuse, Plateformes de Métabolomique et de Criblage Cellulaire Haut Débit, 94805 Villejuif, France. 7- Université Paris-Saclay, Gustave Roussy, U1356 Next Generation Immuno-Oncology Research, 94805 Villejuif, France

Citation: Cancer Cell July 2026

A Patient-Derived Screen Identifies HDAC Inhibitors as Enhancers of Phagocytosis and Potent Immunotherapy Partners

(1) Khalaj M (2) Burden AT (3) Gutierrez ML (4) Hoonsbeen SC (5) Nejad P (6) Raveh T (7) Young JS (8) Fattahi F (9) Weissman IL

Cancer immunology research

(1) Khalaj M (2) Burden AT (3) Gutierrez ML (4) Hoonsbeen SC (5) Nejad P (6) Raveh T (7) Young JS (8) Fattahi F (9) Weissman IL

Cancer immunology research

Glioblastoma multiforme (GBM) is a lethal brain tumor with limited treatment options. Tumor-associated macrophages and microglia (TAMs) drive immune suppression and tumor progression, making them a key therapeutic target for GBM. Enhancing TAM phagocytosis in GBM has shown promise, particularly with innate checkpoint inhibitors, such as CD47-blocking antibodies. However, small molecule approaches, which offer tunable and potentially synergistic mechanisms, remain underexplored in this context. In this study, we conducted a large-scale small molecule screen on primary TAMs isolated directly from GBM patient tumors, testing 1,365 compounds to identify drugs that enhance TAM phagocytosis. This screen revealed enrichment for histone deacetylase (HDAC)-targeting drugs among the top hits. HDAC inhibitors enhanced phagocytosis of cancer cells across multiple primary human TAM-GBM combinations, and synergized with CD47 blockade ex vivo. In a xenograft GBM model, Pracinostat suppressed tumor growth and extended survival, with additive benefit when combined with CD47 antibodies. RNA-sequencing and H3K27Ac CUT&Tag profiling of Pracinostat-treated TAMs in vivo revealed a two-tier mechanism: transcriptional reprogramming toward a pro-inflammatory state via NF-_B activation, and epigenetic priming of Fc_R-mediated phagocytic machinery, providing a mechanistic basis for the observed synergy with CD47 blockade. Our findings establish a patient-first functional screening platform for identifying TAM-reprogramming therapeutics in GBM, validate HDAC inhibitors as a lead class that potentiates innate checkpoint immunotherapy, and provide additional candidate compounds for clinical investigation.

Author Info: (1) Stanford Medicine Stanford United States. ROR: https://ror.org/03mtd9a03 (2) Stanford Medicine United States. ROR: https://ror.org/03mtd9a03 (3) University of California, San F

Author Info: (1) Stanford Medicine Stanford United States. ROR: https://ror.org/03mtd9a03 (2) Stanford Medicine United States. ROR: https://ror.org/03mtd9a03 (3) University of California, San Francisco San Francisco United States. ROR: https://ror.org/043mz5j54 (4) University of California San Francisco Medical Center San Francisco United States. ROR: https://ror.org/01t8svj65 (5) Stanford Medicine Stanford United States. ROR: https://ror.org/03mtd9a03 (6) Stanford University California 94305-5439, CA United States. ROR: https://ror.org/00f54p054 (7) University of California, San Francisco San Francisco, CA United States. ROR: https://ror.org/043mz5j54 (8) University of California, San Francisco San Francisco, CA United States. ROR: https://ror.org/043mz5j54 (9) Stanford University Stanford University, CA United States. ROR: https://ror.org/00f54p054

Citation: Cancer Immunol Res 2026 Jul 14 Epub07/14/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42446904

Tim-3 Sustains Tumor Treg Stability and Function, Limiting Checkpoint Blockade Therapy Efficacy

(1) Banerjee H (2) Onyekachi OV (3) Nieves-Rosado H (4) Murter BM (5) Kulkarni A (6) Pandey SP (7) Cardona E (8) Dougherty JE (9) Li H (10) Upadhyay P (11) Hinterleitner R (12) Ferris RL (13) Kane LP

Cancer immunology research

(1) Banerjee H (2) Onyekachi OV (3) Nieves-Rosado H (4) Murter BM (5) Kulkarni A (6) Pandey SP (7) Cardona E (8) Dougherty JE (9) Li H (10) Upadhyay P (11) Hinterleitner R (12) Ferris RL (13) Kane LP

Cancer immunology research

Regulatory T cells (Treg) act as a powerful barrier to effective antitumor immunity. Although manipulating Treg is a promising anticancer strategy, doing so while sparing general immune tolerance has been a challenge. Identifying factors specifically expressed in tumor-infiltrating Treg is therefore important for better understanding cancer pathogenesis and identifying novel therapeutic targets that enhance antitumor immunity. We show that T cell Immunoglobulin and Mucin 3 (Tim-3) expression on tumor Treg is required for the function and survival of these cells, in part through Akt and FOXO1 signaling. Deleting Tim-3 in Treg leads to delayed tumor-specific T-cell exhaustion and lower tumor burden, without altering peripheral homeostasis. Similar effects were noted when Tim-3 was only deleted from half of the Treg or when deletion was delayed until after tumor inoculation. Moreover, Treg-specific deletion of Tim-3 cooperated with PD-1 checkpoint blockade to sensitize an immunotherapy-resistant tumor model. In addition, a decrease in Tim-3+ tumor Treg correlated with responsiveness to PD-1/LAG-3 combination checkpoint blockade in a human clinical trial. Overall, our data provide evidence that Tim3-expressing Treg are a promising target to modulate tumor-specific immune responses.

Author Info: (1) University of Pittsburgh Pittsburgh, PA United States. ROR: https://ror.org/01an3r305 (2) University of Pittsburgh Pittsburgh, PA United States. ROR: https://ror.org/01an3r305

Author Info: (1) University of Pittsburgh Pittsburgh, PA United States. ROR: https://ror.org/01an3r305 (2) University of Pittsburgh Pittsburgh, PA United States. ROR: https://ror.org/01an3r305 (3) University of Pittsburgh Pittsburgh, PA United States. ROR: https://ror.org/01an3r305 (4) University of Pittsburgh Pittsburgh, PA United States. ROR: https://ror.org/01an3r305 (5) University of North Carolina at Chapel Hill Chapel Hill, NC United States. ROR: https://ror.org/0130frc33 (6) University of Pittsburgh Pittsburgh, PA United States. ROR: https://ror.org/01an3r305 (7) University of Pittsburgh Pittsburgh, PA United States. ROR: https://ror.org/01an3r305 (8) University of Pittsburgh Pittsburgh, PA United States. ROR: https://ror.org/01an3r305 (9) University of Pittsburgh Pittsburgh, PA United States. (10) University of North Carolina at Chapel Hill Chapel Hill, NC United States. ROR: https://ror.org/0130frc33 (11) University of Pittsburgh Pittsburgh, PA United States. ROR: https://ror.org/01an3r305 (12) University of North Carolina Hospitals Chapel Hill, NC United States. ROR: https://ror.org/0355zfr67 (13) University of Pittsburgh Pittsburgh, PA United States. ROR: https://ror.org/01an3r305

Citation: Cancer Immunol Res 2026 Jul 15 Epub07/15/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42455126

Mutant KRAS peptide vaccine with dual checkpoint blockade in metastatic colorectal cancer: a phase I trial

(1) Wang HH (2) Huff AL (3) Haldar SD (4) Berg M (5) Thoburn C (6) Heumann TR (7) Anders RA (8) Barrett B (9) Bever KM (10) Pishvaian MJ (11) Lee V (12) Le DT (13) Christenson ES (14) Baretti M (15) Yarchoan M (16) Laheru D (17) Thomas A (18) Durham JN (19) Nauroth JM (20) Lu J (21) Wang H (22) Jaffee EM (23) Azad NS (24) Zaidi N

Nature communications - Open Access

Immune checkpoint inhibitors (ICIs) have limited activity in mismatch repair proficient or microsatellite stable (MMRp/MSS) colorectal cancer (CRC). KRAS mutations, present in approximately 40% of these cancers, can generate neoantigens that are targets for therapeutic vaccines. In this single-arm, phase I study (NCT04117087), we evaluated mKRAS-VAX, a pooled mutant KRAS (mKRAS) peptide vaccine targeting six KRAS mutations with nivolumab and ipilimumab in 13 patients with pretreated metastatic MMRp/MSS CRC. Both primary endpoints of safety and immunogenicity (within 17 weeks post-vaccination) were met. Secondary endpoints included treatment efficacy defined by RECIST v1.1 criteria. All adverse events attributed to mKRAS-VAX were grade 1 or 2, and the addition of mKRAS-VAX did not increase the frequency of severe immune-related adverse events beyond the expected profile of dual ICIs alone. mKRAS-VAX elicited an increase in tumor-specific mKRAS-reactive T-cells in 8/12 biomarker-evaluable patients (75%) by direct ex vivo IFN_ ELISpot and in 12 patients (100%) following in vitro expansion. Our findings support further development of mKRAS vaccines with ICIs for advanced MMRp/MSS CRC.

Author Info: (1) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. Johns Hopkins Convergence Institute, Johns Hopkins University S

Author Info: (1) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University of Medicine, Baltimore, MD, USA. (2) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University of Medicine, Baltimore, MD, USA. (3) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University of Medicine, Baltimore, MD, USA. Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (4) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. (5) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University of Medicine, Baltimore, MD, USA. (6) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University of Medicine, Baltimore, MD, USA. Department of Hematology/Oncology, Department of Internal Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. (7) Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University of Medicine, Baltimore, MD, USA. Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (8) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University of Medicine, Baltimore, MD, USA. (9) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University of Medicine, Baltimore, MD, USA. (10) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. (11) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. (12) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University of Medicine, Baltimore, MD, USA. (13) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University of Medicine, Baltimore, MD, USA. (14) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University of Medicine, Baltimore, MD, USA. (15) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University of Medicine, Baltimore, MD, USA. (16) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University of Medicine, Baltimore, MD, USA. (17) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. (18) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University of Medicine, Baltimore, MD, USA. (19) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University of Medicine, Baltimore, MD, USA. (20) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. (21) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. (22) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University of Medicine, Baltimore, MD, USA. (23) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. nilo.azad@jhu.edu. Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. nilo.azad@jhu.edu. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University of Medicine, Baltimore, MD, USA. nilo.azad@jhu.edu. (24) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. nzaidi1@jhmi.edu. Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. nzaidi1@jhmi.edu. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University of Medicine, Baltimore, MD, USA. nzaidi1@jhmi.edu.

Citation: Nat Commun 2026 Jun 23 Epub06/23/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42336869

A distinct antigen presentation pathway drives potent T cell immunity in lipid nanoparticle-based mRNA vaccines

(1) Muro R (2) Wang S (3) Ito-Kureha T (4) Huynh HH (5) Kobiyama K (6) Sugita T (7) Okamoto K (8) Nakano K (9) Okamura T (10) Kubo M (11) Ishii KJ (12) Nitta T (13) Takayanagi H

Science advances - Open Access | Free PMC Article

(1) Muro R (2) Wang S (3) Ito-Kureha T (4) Huynh HH (5) Kobiyama K (6) Sugita T (7) Okamoto K (8) Nakano K (9) Okamura T (10) Kubo M (11) Ishii KJ (12) Nitta T (13) Takayanagi H

Science advances - Open Access | Free PMC Article

Lipid nanoparticle-encapsulated mRNA (mRNA-LNP) vaccines trigger the potent differentiation of antigen-specific cytotoxic CD8 T cells in addition to antibody production. Despite its high immunogenicity, the cellular mechanisms by which mRNA-LNP induces such unusual immune responses remain largely unclear. Here, we show that mRNA-LNP induces potent and long-lasting CD8 T cell expansion through an antigen presentation mechanism that differs from that of conventional adjuvants. In mice immunized with mRNA-LNP, the number of antigen-specific CD8 T cells was one order of magnitude higher than that induced by combining antigen proteins with immunostimulants such as lipopolysaccharide or polyinosinic:polycytidinic acid. Intramuscularly administered mRNA-LNPs were mainly taken up by migratory type 2 conventional dendritic cells in draining lymph nodes, resulting in notably strong and persistent antigen presentation through major histocompatibility complex class I. Furthermore, CD8 T cell induction by mRNA-LNP required migratory dendritic cells but not the traditional cross-presentation pathway that is otherwise essential for antiviral and antitumor immunity. Thus, the mRNA-LNP formulation exerts unconventional immune responses through a different antigen-presentation pathway from conventional component vaccines.

Author Info: (1) Department of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan. Division of Molecular Pathology, Research Institute for Bi

Author Info: (1) Department of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan. Division of Molecular Pathology, Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba, Japan. (2) Department of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan. (3) Department of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan. (4) Division of Molecular Pathology, Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba, Japan. (5) Division of Vaccine Science, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan. International Vaccine Design Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan. Division of Rheumatology, Department of Medicine, University of California San Diego, La Jolla, CA, United States. (6) Department of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan. (7) Department of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan. Division of Immune Environment Dynamics, Cancer Research Institute, Kanazawa University, Kanazawa, Japan. Immune Network Research Unit, Institute for Frontier Science Initiative InFiniti, Kanazawa University, Kanazawa, Japan. (8) Department of Laboratory Animal Medicine, National Institute of Global Health and Medicine, Japan Institute for Health and Security (JIHS), Tokyo, Japan. (9) Department of Laboratory Animal Medicine, National Institute of Global Health and Medicine, Japan Institute for Health and Security (JIHS), Tokyo, Japan. (10) Kyoto University Immunomonitoring Center, Liaison Office, Kyoto University, Kyoto, Japan. Department of Immunology, Graduate School of Medicine, Kyoto University, Kyoto, Japan. (11) Division of Vaccine Science, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan. International Vaccine Design Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan. (12) Department of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan. Division of Molecular Pathology, Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba, Japan. (13) Department of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan.

Citation: Sci Adv 2026 Jul 17 12:eaec7827 Epub07/17/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42467780

IL7-Receptor-Targeted CAR T-Cell Therapy for T-Cell Acute Lymphoblastic Leukemia

(1) Hocine HR (2) Ganbaatar U (3) Amador-Molina A (4) Banerjee S (5) Misawa K (6) Rubino V (7) Ankola P (8) Fong C (9) Xiong Y (10) Vista WR (11) Bellis RY (12) Chintala NK (13) Curran KJ (14) Sulis ML (15) Park JH (16) Kung AL (17) Adusumilli PS

Nature communications - Open Access

On the basis that T-cell acute lymphoblastic leukemia (T-ALL) cells overexpress IL7 receptor (IL7R), which promotes resistance to chemotherapy and disease relapse, here we develop IL7R_ (CD127)-targeted chimeric antigen receptor (CAR) T cells with low- and high-affinity single-chain variable fragments. We establish the antitumor efficacy of CD127 CAR against T-ALL cells in vitro, in female mouse models of T-ALL, and against blasts from patients with T-ALL using the patients' own T cells transduced with CD127 CAR. Antitumor efficacy is higher with low-affinity CAR T cells than high-affinity CAR T cells, albeit with fratricide of CAR T cells following eradication of CD127-overexpressing blasts. CRISPR-Cas9 knockout of CD127 eliminates fratricide at the risk of prolonged lymphopenia in vivo. To overcome fratricide, we investigate short-term (_<_7 days) co-culture with or without dasatinib, a tyrosine kinase inhibitor, versus a natural selection method (10 days) and demonstrate that co-culturing with dasatinib facilitates higher CAR T-cell yield, improved fitness, and preserved functionality. In vivo, dasatinib can be used to temporarily and reversibly suppress CAR T-cell activity. With this supporting translational data, we are initiating a trial with low-affinity CD127 CAR T cells for adult and pediatric patients with relapsed or refractory T-ALL.

Author Info: (1) Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (2) Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer

Author Info: (1) Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (2) Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (3) Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (4) Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (5) Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (6) Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (7) Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (8) Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York, USA. (9) Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (10) Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (11) Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (12) Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (13) Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York, USA. (14) Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York, USA. (15) Cellular Therapy Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, USA. (16) Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York, USA. (17) Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. adusumip@mskcc.org. Cellular Therapy Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, USA. adusumip@mskcc.org.

Citation: Nat Commun 2026 Jul 15 Epub07/15/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42457686

Dendritic cells control tertiary lymphoid structure development and maintenance in cancer

(1) Mattiuz R (2) Boumelha J (3) Aerakis E (4) Le Berichel J (5) Hamon P (6) Halasz L (7) Vaidya A (8) Soong BY (9) Radkevich E (10) Kim HM (11) Park MD (12) Donne R (13) Troncoso L (14) Kaplan RA (15) Hennequin C (16) Hernndez-Verdin I (17) Lpez L (18) Rentzeperis F (19) D'Souza D (20) Kaiza ME (21) MacFawn IP (22) Belabed M (23) Mestrallet G (24) Humblin E (25) Merand R (26) Hegde S (27) Lone JC (28) Ioannou G (29) Ozbey S (30) Figueiredo I (31) Tepper A (32) Merarda H (33) Serhan N (34) Schaefer MM (35) An J (36) Ohara RA (37) Nemeth E (38) Goldstein S (39) Reid AM (40) Noureddine M (41) Tabachnikova A (42) Piperno GM (43) Tsoumakidou M (44) Ahmed J (45) Polydorides AD (46) Bhardwaj N (47) Lujambio A (48) Chen Z (49) Gonzalez Kozlova E (50) Kim-Schulze S (51) Brody JD (52) Schotsaert M (53) Moussion C (54) Gnjatic S (55) Roudko V (56) Ginhoux F (57) Murphy KM (58) Sauts-Fridman C (59) Fridman WH (60) Brown BD (61) Marron TU (62) Benvenuti F (63) Cyster JG (64) Salmon H (65) Bruno TC (66) Joshi NS (67) Kamphorst AO (68) Merad M

Science

Tertiary lymphoid structures (TLSs) are associated with immunotherapy response, yet the mechanisms controlling their formation and maintenance remain unclear. Using spatial transcriptomics and multiplex imaging across human tumors, we found that CCR7(+) mature dendritic cells (DCs) accumulate in TLSs. In a mouse non-small cell lung cancer model that forms mature TLSs, we show that early TLS development requires interferon-_ (IFN-_)-driven type 1 conventional dendritic cell (cDC1) maturation, migration to tumor-draining lymph nodes (tdLNs), and T cell recruitment. As tumors progress, TLSs persist independently of tdLN T cell egress, coinciding with cDC1 accumulation within intratumoral CCL19 stromal hubs. There, cDC1-major histocompatibility complex class 1 (MHC-I) and -MHC-II concomitant antigen presentation, along with CD40 signaling, sustain TLS, T follicular helper (T(FH)) cell pool, germinal centers, and tumor-specific immunoglobulin G (IgG). These findings highlight local mature cDC1s as key TLS orchestrators and potential targets to enhance antitumor TLS function.

Author Info: (1) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn Schoo

Author Info: (1) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (2) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (3) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Institute for Bioinnovation, "Alexander Fleming" Biomedical Sciences Research Center, Vari, Greece. (4) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (5) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (6) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (7) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (8) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (9) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (10) Tumor Microenvironment Center, Department of Immunology, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA. (11) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (12) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Tisch Cancer Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (13) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (14) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (15) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (16) Department of Immunology, Inflammation, Complement and Cancer, Centre de Recherche des Cordeliers, Sorbonne Universit, INSERM, Universit Paris Cit, Paris, France. (17) Cellular Immunology, International Centre for Genetic Engineering and Biotechnology, ICGEB, Trieste, Italy. (18) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (19) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (20) Tumor Microenvironment Center, Department of Immunology, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA. (21) Tumor Microenvironment Center, Department of Immunology, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA. Department of Biology, Grove City College, Grove City, PA, USA. (22) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (23) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Tisch Cancer Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (24) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (25) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (26) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (27) GIMM, Gulbenkian Institute for Molecular Medicine and Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal. (28) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (29) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (30) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (31) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (32) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (33) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (34) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (35) Howard Hughes Medical Institute and Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, USA. (36) Department of Pathology and Immunology, Washington University in St. Louis School of Medicine, St. Louis, MO, USA. (37) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (38) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (39) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (40) Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Global Health and Emerging Pathogens Institute and Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (41) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (42) Cellular Immunology, International Centre for Genetic Engineering and Biotechnology, ICGEB, Trieste, Italy. (43) Institute for Bioinnovation, "Alexander Fleming" Biomedical Sciences Research Center, Vari, Greece. (44) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (45) Henry D. Janowitz Division of Gastroenterology, Department of Medicine, and Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (46) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Tisch Cancer Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (47) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Tisch Cancer Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (48) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (49) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (50) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (51) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (52) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. GIMM, Gulbenkian Institute for Molecular Medicine and Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal. Global Health and Emerging Pathogens Institute and Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (53) Genentech, South San Francisco, CA, USA. (54) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (55) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (56) Paris-Saclay University, Gustave Roussy, INSERM U1015, Villejuif, France. (57) Department of Pathology and Immunology, Washington University in St. Louis School of Medicine, St. Louis, MO, USA. (58) Department of Immunology, Inflammation, Complement and Cancer, Centre de Recherche des Cordeliers, Sorbonne Universit, INSERM, Universit Paris Cit, Paris, France. (59) Department of Immunology, Inflammation, Complement and Cancer, Centre de Recherche des Cordeliers, Sorbonne Universit, INSERM, Universit Paris Cit, Paris, France. (60) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (61) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Institute for Thoracic Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (62) Cellular Immunology, International Centre for Genetic Engineering and Biotechnology, ICGEB, Trieste, Italy. (63) Howard Hughes Medical Institute and Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, USA. (64) Institut Curie, Paris, France. (65) Tumor Microenvironment Center, Department of Immunology, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA. (66) Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. (67) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Tisch Cancer Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Graduate Education, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (68) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Citation: Science 2026 Jul 16 393:eady1678 Epub07/16/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42462020

Tryptophan degradation by intestinal Bacteroides induces anti-tumor immunity and limits melanoma growth Spotlight

(1) Olea XD (2) Beede K (3) Pereira G (4) Scott D (5) Petucci C (6) Martens E (7) Rodionov D (8) Shah A (9) Martinez MP (10) Kim H (11) Sharma AK (12) Martin A (13) Zhang T (14) Faries MB (15) Hamid O (16) Devkota S (17) Osterman A (18) Knott S (19) Voest EE (20) Ajami NJ (21) Wargo J (22) Ramer-Tait AE (23) Ronai ZA

Cell reports. Medicine - Open Access

Olea and Beede et al. identified Bacteroides rodentium and Bacteroides uniformis (found in mice and humans, respectively) as gut microbes that induced antitumor immunity and inhibited tumor growth in melanoma mouse models. These strains expressed tryptophanase A (TnaA) and aromatic aminotransferases (ArAT) that degraded tryptophan into indoles. TnaA loss in B. uniformis abrogated antitumor activity, whereas indole administration increased CD8⁺ T cell infiltration and restrained tumor growth, independent of AhR signaling. Elevated levels of ArAT and TnaA were found in patients with melanoma who responded to ICB.

Contributed by Shishir Pant

Cell reports. Medicine - Open Access

ABSTRACT: Study of gut microbiota control of anti-tumor immunity (ATI) identifies Bacteroides rodentium and the human-related Bacteroides uniformis species to be capable of inducing ATI and limiting melanoma development in germ-free (GF), complex microbiome, or wild-type (WT) mice. Enhanced CD8(+) T cell infiltration within tumors of mice harboring B. rodentium coincides with increased expression of immune-stimulating pathways. Metabolomic analyses identify lower tryptophan levels in the cecal samples of GF mice harboring B. rodentium. In silico genomic reconstruction reveals that B. rodentium and B. uniformis harbor tryptophanase A (TnaA) and aromatic aminotransferase genes, which degrade tryptophan to indoles. Administration of B. uniformis harboring TnaA mutant fails to inhibit melanoma growth. Notably, administration of indoles effectively induces ATI and inhibits melanoma development. Correspondingly, the levels of bacterially encoded tryptophan-degrading enzymes are higher in cohorts of patients with melanoma responding to immunotherapy. These findings identify indoles as tryptophan breakdown products capable of inducing ATI resulting in melanoma inhibition.

Author Info: (1) Translational Research Institute, Elinor and Rendall Department of Surgery, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA; Department of Biomedical Sciences, Cedars S

Author Info: (1) Translational Research Institute, Elinor and Rendall Department of Surgery, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA; Department of Biomedical Sciences, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA; Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA. (2) Department of Food Science and Technology, Nebraska Food for Health Center, University of Nebraska-Lincoln, Lincoln, NE 68588, USA. (3) Department of Microbiology & Immunology, University of Michigan Medical School, Ann Arbor, MI 48109, USA. (4) Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA. (5) Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. (6) Department of Microbiology & Immunology, University of Michigan Medical School, Ann Arbor, MI 48109, USA. (7) Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA. (8) Translational Research Institute, Elinor and Rendall Department of Surgery, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA. (9) Division of Molecular Oncology & Immunology, the Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands. (10) Translational Research Institute, Elinor and Rendall Department of Surgery, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA. (11) Human Microbiome Research Institute, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA. (12) Human Microbiome Research Institute, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA. (13) Division of Cancer Epidemiology & Genetics, National Cancer Institute, Rockville, MD 20892, USA. (14) The Angeles Clinic and Research Institute, Cedars Sinai Medical Center, Los Angeles, CA 90025, USA. (15) The Angeles Clinic and Research Institute, Cedars Sinai Medical Center, Los Angeles, CA 90025, USA. (16) Department of Biomedical Sciences, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA; Human Microbiome Research Institute, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA. (17) Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA. (18) Translational Research Institute, Elinor and Rendall Department of Surgery, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA. (19) Division of Molecular Oncology & Immunology, the Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands. (20) Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (21) Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (22) Department of Food Science and Technology, Nebraska Food for Health Center, University of Nebraska-Lincoln, Lincoln, NE 68588, USA. Electronic address: aramer-tai2@unl.edu. (23) Translational Research Institute, Elinor and Rendall Department of Surgery, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA; Department of Biomedical Sciences, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA. Electronic address: zeev.ronai@csmc.edu.

Citation: Cell Rep Med 2026 Jul 14 102921 Epub07/14/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42447866

In vivo engineering tumor cells to a universal "all-in-one" cancer vaccine with full antigen spectrum Spotlight

(1) Wang W (2) Huang Y (3) Zhang J (4) Wang Y (5) Yu Z (6) Zhang F (7) Zhang H (8) Zhang R (9) Zhong R (10) Zhong H (11) Zhang L (12) Liu C (13) Shen C (14) Li Z (15) Wang M (16) Yang X

Science advances - Open Access | Free PMC Article

Wang et al. engineered an “all-in-one” cancer cell-derived vaccine (UniCVac) by co-expressing CIITA, NLRC5, CD80, and IL-2 in tumor cells to mimic professional APCs with both HLA-I and HLA-II antigen presentation, co-stimulation, and T cell growth signal. UniCVac cells presented antigens to both CD4⁺ and CD8⁺ T cells in vitro, driving activation and proliferation similar to APCs. UniCVac achieved potent antitumor activity in therapeutic (NSG) models, and induced polyclonal tumor-specific T cell responses, reprogrammed the immunosuppressive TIME to be immune-permissive, and enhanced tumor control in B16 and MC38 tumor models.

Contributed by Shishir Pant

(1) Wang W (2) Huang Y (3) Zhang J (4) Wang Y (5) Yu Z (6) Zhang F (7) Zhang H (8) Zhang R (9) Zhong R (10) Zhong H (11) Zhang L (12) Liu C (13) Shen C (14) Li Z (15) Wang M (16) Yang X

Science advances - Open Access | Free PMC Article

ABSTRACT: Cancer vaccines offer a promising strategy to initiate de novo T cell responses or enhance existing ones, either functioning independently or synergizing with T cell-modulating therapeutics to reduce tumor burden. The clinical development of cancer vaccines faces challenges such as limited antigen coverage, insufficient antigen presentation, immune suppressive microenvironment, and the availability of personalized vaccines. In this study, we developed a universal "all-in-one" cancer cell-derived vaccine (UniCVac) with comprehensive antigen spectrum coverage by programming tumor cells into antigen-presenting cells (APCs) through the codelivery of CIITA, NLRC5, CD80, and IL-2. This reprogramming mimics the professional APC phenotype, providing simultaneous HLA-I and HLA-II antigen presentation, costimulation, and T cell proliferation signals. These tumor-derived UniCVac can directly activate both CD4(+) and CD8(+) T cells in vitro, independent of APCs. In addition, their costimulation and T cell growth-stimulating capabilities result in superior CD4(+) and CD8(+) T cell activation and proliferation comparable to traditional APCs, with enhanced PI3K-AKT pathways activation. Single-cell transcriptome analysis confirmed the similarity in cellular subtypes between UniCVac-activated and traditional APC-activated T cells. In mouse models, the UniCVac vaccination reprogramed the tumor microenvironment from immunosuppressive to immune-permissive, induced robust CD4(+) and CD8(+) T cell expansion in both preventive and therapeutic tumor models, and achieved complete tumor regression in vivo. Our approach provides a platform for the development of universal cancer vaccines with full antigen spectrum coverage and the ability to directly activate both CD4(+) and CD8(+) T cells, offering potential combinatorial opportunities with existing T cell-based immunotherapies against cancer.

Author Info: (1) Sheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China. (2) Sheng Yushou Center of Cell B

Author Info: (1) Sheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China. (2) Sheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China. (3) Sheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China. (4) Sheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China. (5) Sheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China. (6) Sheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China. (7) Sheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China. (8) Sheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China. (9) Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. (10) Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. (11) Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. (12) Cellular and Molecular Medicine, School of life sciences, University of Bristol, Bristol, UK. (13) Department of mathematics and statistics, Northeastern University at Qinhuangdao, Qinhuangdao, China. (14) Department of Biomedical Sciences, University College London, London, UK. (15) Department of Gynaecology and Obstetrics, Shanghai Pudong New Area People's Hospital, Shanghai, China. (16) Sheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China. Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Department of Gynaecology and Obstetrics, Shanghai Pudong New Area People's Hospital, Shanghai, China. Engineering Research Center of Cell & Therapeutic Antibody, MOE, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China. State Key Laboratory of Microbial Metabolism, Joint International Research Laboratory of Metabolic & Developmental Sciences, Shanghai Jiao Tong University, Shanghai, China.

Citation: Sci Adv 2026 Jul 10 12:eaee5201 Epub07/08/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42418568

The efficacy of immunotherapy in glioma requires distal B cell responses in tumor-draining lymph nodes Spotlight

(1) Kim Y (2) Kang I (3) Kang BH (4) Park WH (5) Kim CW (6) Kim HJ (7) La J (8) Kwon MS (9) Park SH (10) Im SH (11) Kim HC (12) Ku KB (13) Kim M (14) Oh JE (15) Lee HK

Science immunology

Kim et al. showed that anti-CTLA-4 efficacy in orthotopic murine glioblastoma (GBM) models was abolished by B cell deficiency and tdLN removal. In WT mice, anti-CTLA-4 increased B cell numbers and GC reactions in tdLNs, but not in the TIME, and therapeutic efficacy required CD4⁺ T cell help to B cells. While maintaining tumor-reactive CD4⁺ T cell function in the TIME, in tdLNs, anti-CTLA-4 therapy boosted T_FH cell differentiation to support GC B cell clonal expansion and generation of antibody-secreting cells producing tumor-binding class-switched IgG1 antibodies that promoted macrophage-mediated phagocytosis of glioma cells via Fc receptor signaling.

Contributed by Paula Hochman

(1) Kim Y (2) Kang I (3) Kang BH (4) Park WH (5) Kim CW (6) Kim HJ (7) La J (8) Kwon MS (9) Park SH (10) Im SH (11) Kim HC (12) Ku KB (13) Kim M (14) Oh JE (15) Lee HK

Science immunology

ABSTRACT: Humoral immunity, mediated by B cells that mature in germinal centers in lymph nodes (LNs), is essential for adaptive immune responses, but its role in antitumor immunity and responses to immunotherapy remain unclear. Here, we show that activation of B cells in tumor-draining deep cervical LNs (dcLNs) is necessary for the efficacy of CTLA-4 (cytotoxic T lymphocyte-associated protein 4) immune checkpoint blockade in glioma in vivo. Anti-CTLA-4 therapy enhanced T follicular helper cell (T(FH) cell) expansion in dcLNs, leading to germinal center B cell responses, immunoglobulin G (IgG) class switching, and the generation of glioma-reactive antibodies. Glioma-bearing mice lacking antibody-secreting cells did not benefit from CTLA-4 blockade. Distally secreted IgG accumulated in the tumor microenvironment and promoted glioma cell phagocytosis in vivo. These findings define a B cell-dependent mechanism underlying CTLA-4-mediated control of glioma and provide a conceptual framework for future therapeutic strategies in tumor.

Author Info: (1) Laboratory of Host Defenses, Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea. (2) Laboratory of Host D

Author Info: (1) Laboratory of Host Defenses, Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea. (2) Laboratory of Host Defenses, Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea. (3) Laboratory of Host Defenses, Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea. Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea. (4) Laboratory of Host Defenses, Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea. Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea. (5) Laboratory of Host Defenses, Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea. (6) Laboratory of Host Defenses, Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea. (7) Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea. (8) Laboratory of Host Defenses, Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea. Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea. (9) Laboratory of Host Defenses, Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea. Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea. (10) Laboratory of Host Defenses, Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea. (11) Laboratory of Host Defenses, Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea. (12) Laboratory of Host Defenses, Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea. Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea. Department of Convergent Research of Emerging Virus Infection, Korea Research Institute of Chemical Technology, Daejeon, Republic of Korea. (13) Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea. (14) Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea. (15) Laboratory of Host Defenses, Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea. Regenerative Medical Research Institute (reMRI) for Aging-Related Diseases, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea.

Citation: Sci Immunol 2026 Jul 10 11:eadz2494 Epub07/10/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42430444

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