Experimental Immunotherapy - ACIR Journal Articles

Generalizable AI predicts immunotherapy outcomes across cancers and treatments

(1) Shen W (2) Moon I (3) Nguyen TH (4) Li MM (5) Huang Y (6) Nair N (7) Marbach D (8) Zitnik M

Immune checkpoint inhibitors (ICIs) are a standard treatment across cancers, yet most patients do not respond, and existing biomarkers generalize poorly across tumor types and therapies. Here we present COMPASS, a pan-cancer foundation model that predicts immunotherapy response from bulk tumor transcriptomes using a concept bottleneck transformer. COMPASS encodes gene expression through 44 biologically grounded immune concepts representing immune cell states, tumor-microenvironment interaction and signaling pathways. Trained on 10,184 tumors across 33 cancer types, COMPASS achieves better average performance than 22 methods across 16 clinical cohorts spanning seven cancers and six ICIs, improving accuracy by 8.5% and area under the precision-recall curve by 15.7% on average across cohorts. COMPASS generalizes to cancer types and treatments not represented during fine-tuning and may inform indication selection and patient stratification. In survival analyses, patients classified by COMPASS as responders had longer overall survival (hazard ratio_=_4.7, P_<_0.0001). Personalized response maps connect gene expression to immune concepts, identifying programs associated with response and resistance; in immune-inflamed non-responders, COMPASS highlights programs including TGF_ signaling, endothelial exclusion, CD4(+) T cell dysfunction and B cell deficiency. COMPASS predicts immunotherapy response and provides hypothesis-generating mechanistic insight for trial design and translational studies.

Author Info: (1) Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA. College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China. (2) Department of Biome

Author Info: (1) Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA. College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China. (2) Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA. (3) Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. (4) Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA. (5) Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA. (6) Roche Pharma Research and Early Development, Oncology Early Clinical Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, Switzerland. (7) Computational Sciences Center of Excellence, F. Hoffmann-La Roche Ltd., Basel, Switzerland. daniel.marbach.dm1@roche.com. (8) Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA. marinka@hms.harvard.edu. Kempner Institute for the Study of Natural and Artificial Intelligence, Harvard University, Allston, MA, USA. marinka@hms.harvard.edu. Broad Institute of MIT and Harvard, Cambridge, MA, USA. marinka@hms.harvard.edu. Harvard Data Science Initiative, Cambridge, MA, USA. marinka@hms.harvard.edu.

Citation: Nat Med 2026 Jul 3 Epub07/03/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42399673

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Enhancement of ferroptosis in escape variant tumor cells by IFN-γ derived from antigen-specific T cells controls tumor with heterogeneity
Spotlight

(1) Ehara D (2) Yasui K (3) Yoneda M (4) Muraoka D (5) Deng S (6) Miao P (7) Jiang C (8) Sun H (9) Okamoto S (10) Amaishi Y (11) Murota H (12) Ikeda H

Cancer immunology research

To enhance immunotherapy efficacy against escape variant clones, Ehara et al. combined MART-1 TCR-T cells with the ferroptosis inducer RSL3. IFNγ secreted by the TCR-T cells enhanced the susceptibility of melanoma cells to ferroptosis. In mice injected with an equal mix of 526MEL and β2mKO cells, the combination treatment inhibited tumor growth, including reduction of the HLA-negative tumor mass, and significantly increased T cell infiltration compared to controls. In patients with melanoma, high expression of IFNγ signature genes STAT1 and IRF1 and low expression of SLC2A2 (counteracting ferroptosis) predicted better outcomes.

Contributed by Ute Burkhardt

(1) Ehara D (2) Yasui K (3) Yoneda M (4) Muraoka D (5) Deng S (6) Miao P (7) Jiang C (8) Sun H (9) Okamoto S (10) Amaishi Y (11) Murota H (12) Ikeda H

Cancer immunology research

To enhance immunotherapy efficacy against escape variant clones, Ehara et al. combined MART-1 TCR-T cells with the ferroptosis inducer RSL3. IFNγ secreted by the TCR-T cells enhanced the susceptibility of melanoma cells to ferroptosis. In mice injected with an equal mix of 526MEL and β2mKO cells, the combination treatment inhibited tumor growth, including reduction of the HLA-negative tumor mass, and significantly increased T cell infiltration compared to controls. In patients with melanoma, high expression of IFNγ signature genes STAT1 and IRF1 and low expression of SLC2A2 (counteracting ferroptosis) predicted better outcomes.

Contributed by Ute Burkhardt

ABSTRACT: Tumor masses often exhibit heterogeneity, including escape variant clones that lack antigen-presenting machinery and/or tumor antigens, which poses a major challenge to immunotherapy. Ferroptosis, a form of regulated cell death driven by iron-dependent lipid peroxidation, has been shown to effectively induce cell death in various tumor cells. Recent studies have reported that IFN-γ suppresses the expression of System Xc-, thereby enhancing the induction of ferroptosis. Based on this, we hypothesized that combining immunotherapy with ferroptosis inducers could enhance antitumor effects against both antigen-positive and antigen-negative tumor cells. We found that combining RSL3, a ferroptosis inducer, with MART-1-specific TCR-T cells eradicates a heterogeneous tumor model consisting of human melanoma cells and their β2 microglobulin knockout counterparts. In NOG mice, this combination therapy demonstrates a significant antitumor effect against tumors with heterogeneity. These findings suggest that integrating ferroptosis inducers with immunotherapy could overcome the limitations imposed by escape variant tumor clones, offering a promising strategy for cancer treatment.

Author Info: (1) Nagasaki University Nagasaki Japan. ROR: https://ror.org/058h74p94 (2) Nagasaki University Nagasaki Japan. ROR: https://ror.org/058h74p94 (3) Nagasaki University Nagasaki Japan

Author Info: (1) Nagasaki University Nagasaki Japan. ROR: https://ror.org/058h74p94 (2) Nagasaki University Nagasaki Japan. ROR: https://ror.org/058h74p94 (3) Nagasaki University Nagasaki Japan. ROR: https://ror.org/058h74p94 (4) Aichi Cancer Center Research Institute Chikusa-ku, Nagoya, Aichi Japan. (5) Nagasaki University Nagasaki Japan. ROR: https://ror.org/058h74p94 (6) Nagasaki University Nagasaki Japan. ROR: https://ror.org/058h74p94 (7) Nagasaki University Nagasaki Japan. ROR: https://ror.org/058h74p94 (8) Nagasaki University Nagasaki Japan. ROR: https://ror.org/058h74p94 (9) Takara Bio Inc. Kusatsu, Shiga Japan. (10) Takara Bio Inc. Otsu, Shiga Japan. (11) Nagasaki University Nagasaki Japan. ROR: https://ror.org/058h74p94 (12) Nagasaki University Nagasaki, Nagasaki Japan. ROR: https://ror.org/058h74p94

Citation: Cancer Immunol Res 2026 Jul 3 Epub07/03/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42397036

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Neoadjuvant stereotactic body radiation therapy with durvalumab and oleclumab in ER+HER2- breast cancer: a randomized phase 2 trial
Featured

(1) De Caluwé A (2) Desmoulins I (3) Cao K (4) Remouchamps V (5) Baten A (6) Longton E (7) Peignaux K (8) Joaquin Garcia A (9) Venet D (10) Arecco L (11) Agostinetto E (12) Nader-Marta G (13) Denis Z (14) Dhont J (15) Kristanto P (16) Catteau X (17) Larsimont D (18) Salgado R (19) Poortmans P (20) Stagg J (21) Sotiriou C (22) Piccart M (23) Ignatiadis M (24) Romano E (25) Buisseret L

Nature medicine

De Caluwé et al. conducted a phase 2 clinical trial in patients with ER⁺HER2^- breast cancer assessing neoadjuvant chemotherapy with immune-modulating stereotactic body radiation therapy (iSBRT) alone or combined with anti-PD-L1 and anti-CD73 ICB. The addition of single or double ICB improved residual cancer burden and complete response rates. Patients with node-positive, PD-L1-negative tumors containing stromal tumor-infiltrating lymphocytes at baseline benefited most, with treatment modulating the tumor immune microenvironment from cold to hot.

(1) De Caluwé A (2) Desmoulins I (3) Cao K (4) Remouchamps V (5) Baten A (6) Longton E (7) Peignaux K (8) Joaquin Garcia A (9) Venet D (10) Arecco L (11) Agostinetto E (12) Nader-Marta G (13) Denis Z (14) Dhont J (15) Kristanto P (16) Catteau X (17) Larsimont D (18) Salgado R (19) Poortmans P (20) Stagg J (21) Sotiriou C (22) Piccart M (23) Ignatiadis M (24) Romano E (25) Buisseret L

Nature medicine

De Caluwé et al. conducted a phase 2 clinical trial in patients with ER⁺HER2^- breast cancer assessing neoadjuvant chemotherapy with immune-modulating stereotactic body radiation therapy (iSBRT) alone or combined with anti-PD-L1 and anti-CD73 ICB. The addition of single or double ICB improved residual cancer burden and complete response rates. Patients with node-positive, PD-L1-negative tumors containing stromal tumor-infiltrating lymphocytes at baseline benefited most, with treatment modulating the tumor immune microenvironment from cold to hot.

ABSTRACT: Patients with estrogen receptor-positive (ER+), HER2-negative, early breast cancer (BC) have low pathologic complete response (pCR) rates following neoadjuvant chemotherapy. Immune checkpoint inhibitors (ICIs) provide limited benefit in programmed death-ligand 1 (PD-L1)-negative tumors, characterized by an immune-cold tumor microenvironment. Here we hypothesized that immune-modulating stereotactic body radiation therapy (iSBRT; 3 × 8 Gy) could enhance response through tumor microenvironment reprogramming, and that CD73 blockade could further improve efficacy. We conducted a phase 2, randomized, multicenter trial (Neo-CheckRay) in 147 female patients with high-risk, ER+HER2- early BC. Patients received neoadjuvant chemotherapy plus iSBRT alone (No_ICI), with anti-PD-L1 durvalumab (Single_ICI) or with durvalumab plus anti-CD73 oleclumab (Double_ICI). In the intention-to-treat population, the primary endpoint, residual cancer burden 0/1 rate, was 35.4% with No_ICI, 45.1% with Single_ICI and 47.9% with Double_ICI, without statistically significant differences. pCR rates were 16.7%, 29.4% and 33.3%, respectively (P = 0.059). In the per-protocol population (MammaPrint High Risk, n = 131), pCR rates were 16.3%, 32.6% and 35.6%, respectively (P = 0.040). Among PD-L1-negative tumors (n = 91), pCR rates were 3.4%, 28.1% and 30.0%, respectively. No new safety signals were observed. Baseline transcriptomic analysis showed low immune signature expression in PD-L1-negative tumors. Paired baseline and on-treatment biopsies obtained 1 week after iSBRT demonstrated tumor microenvironment reprogramming toward an inflamed phenotype in the iSBRT + anti-PD-L1 arms. These findings suggest that iSBRT + anti-PD-L1 may convert immune-cold ER+HER2- BC into more inflamed tumors and improve response, particularly in PD-L1-negative disease. ClinicalTrials.gov registration: NCT03875573 .

Author Info: (1) Institut Jules Bordet, Hpitaux Universitaires de Bruxelles (H.U.B), Universit Libre de Bruxelles (ULB), Brussels, Belgium. alex.decaluwe@bordet.be. (2) Centre Georges-Franoi

Author Info: (1) Institut Jules Bordet, Hpitaux Universitaires de Bruxelles (H.U.B), Universit Libre de Bruxelles (ULB), Brussels, Belgium. alex.decaluwe@bordet.be. (2) Centre Georges-Franois Leclerc, Universit Bourgogne Europe, Dijon, France. (3) Institut Curie, Paris, France. (4) CHU St Elisabeth, Namur, Belgium. (5) Universitaire Ziekenhuizen Leuven, Leuven, Belgium. (6) Hpital Universitaire St Luc, Brussels, Belgium. (7) Centre Georges-Franois Leclerc, Universit Bourgogne Europe, Dijon, France. (8) Institut Jules Bordet, Hpitaux Universitaires de Bruxelles (H.U.B), Universit Libre de Bruxelles (ULB), Brussels, Belgium. (9) Institut Jules Bordet, Hpitaux Universitaires de Bruxelles (H.U.B), Universit Libre de Bruxelles (ULB), Brussels, Belgium. (10) Institut Jules Bordet, Hpitaux Universitaires de Bruxelles (H.U.B), Universit Libre de Bruxelles (ULB), Brussels, Belgium. (11) Institut Jules Bordet, Hpitaux Universitaires de Bruxelles (H.U.B), Universit Libre de Bruxelles (ULB), Brussels, Belgium. (12) Institut Jules Bordet, Hpitaux Universitaires de Bruxelles (H.U.B), Universit Libre de Bruxelles (ULB), Brussels, Belgium. (13) Institut Jules Bordet, Hpitaux Universitaires de Bruxelles (H.U.B), Universit Libre de Bruxelles (ULB), Brussels, Belgium. (14) Institut Jules Bordet, Hpitaux Universitaires de Bruxelles (H.U.B), Universit Libre de Bruxelles (ULB), Brussels, Belgium. (15) Institut Jules Bordet, Hpitaux Universitaires de Bruxelles (H.U.B), Universit Libre de Bruxelles (ULB), Brussels, Belgium. (16) Institut Jules Bordet, Hpitaux Universitaires de Bruxelles (H.U.B), Universit Libre de Bruxelles (ULB), Brussels, Belgium. (17) Institut Jules Bordet, Hpitaux Universitaires de Bruxelles (H.U.B), Universit Libre de Bruxelles (ULB), Brussels, Belgium. (18) ZAS Hospitals, Antwerp, Belgium. Peter Mac Callum Cancer Centre, Melbourne, Victoria, Australia. (19) Iridium Netwerk, Antwerp, Belgium. University of Antwerp, Antwerp, Belgium. (20) Goodman Cancer Institute, McGill University, Montreal, Quebec, Canada. (21) Institut Jules Bordet, Hpitaux Universitaires de Bruxelles (H.U.B), Universit Libre de Bruxelles (ULB), Brussels, Belgium. (22) Institut Jules Bordet, Hpitaux Universitaires de Bruxelles (H.U.B), Universit Libre de Bruxelles (ULB), Brussels, Belgium. (23) Institut Jules Bordet, Hpitaux Universitaires de Bruxelles (H.U.B), Universit Libre de Bruxelles (ULB), Brussels, Belgium. (24) Institut Curie, Paris, France. (25) Institut Jules Bordet, Hpitaux Universitaires de Bruxelles (H.U.B), Universit Libre de Bruxelles (ULB), Brussels, Belgium.

Citation: Nat Med 2026 Jun 25 Epub06/25/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42350643

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CDK4/6 inhibition enhances CAR-T cell therapy in solid tumors Spotlight

(1) Lelliott EJ (2) Naddaf J (3) Lu KH (4) Cummins KD (5) Ramsbottom KM (6) Reynolds DS (7) Taylor M (8) Ambani K (9) Munoz I (10) Jackson S (11) Li J (12) Chan CW (13) Britt KL (14) Beavis PA (15) Goel S (16) Oliaro J

Molecular therapy - Open Access | Free PMC Article

Lelliott et al. showed that the CDK4/6 inhibitor trilaciclib enhanced the metabolic fitness of and cytotoxicity by human CD19 CAR-T cells while reducing their proliferation in vitro. In mice with RB-proficient, trilaciclib-sensitive, CD19⁺ leukemia, trilaciclib plus CD19 CAR-T cell therapy was more efficacious than monotherapies. In mouse models of solid (breast, ovarian) tumors, even tumors poorly sensitive to trilaciclib alone responded better to tumor antigen-directed CAR-T cells plus trilaciclib than to the single therapies. Trilaciclib reduced suppressive Treg numbers and boosted CAR-T cell persistence, tumor trafficking, and cytotoxic function per cell in solid tumors.

Contributed by Paula Hochman

(1) Lelliott EJ (2) Naddaf J (3) Lu KH (4) Cummins KD (5) Ramsbottom KM (6) Reynolds DS (7) Taylor M (8) Ambani K (9) Munoz I (10) Jackson S (11) Li J (12) Chan CW (13) Britt KL (14) Beavis PA (15) Goel S (16) Oliaro J

Molecular therapy - Open Access | Free PMC Article

Lelliott et al. showed that the CDK4/6 inhibitor trilaciclib enhanced the metabolic fitness of and cytotoxicity by human CD19 CAR-T cells while reducing their proliferation in vitro. In mice with RB-proficient, trilaciclib-sensitive, CD19⁺ leukemia, trilaciclib plus CD19 CAR-T cell therapy was more efficacious than monotherapies. In mouse models of solid (breast, ovarian) tumors, even tumors poorly sensitive to trilaciclib alone responded better to tumor antigen-directed CAR-T cells plus trilaciclib than to the single therapies. Trilaciclib reduced suppressive Treg numbers and boosted CAR-T cell persistence, tumor trafficking, and cytotoxic function per cell in solid tumors.

Contributed by Paula Hochman

ABSTRACT: CDK4/6 inhibitors promote anti-tumor immunity through diverse mechanisms, positioning them as promising adjuvants to cancer immunotherapies. While CDK4/6 inhibitors have demonstrated strong synergy with immune checkpoint inhibitors across numerous preclinical cancer models, their combination with CAR-T cell therapy remains unexplored. In this study, we examined the efficacy of combined CDK4/6 inhibition (trilaciclib) and CAR-T therapy across a range of preclinical blood and solid cancer models. In vitro, trilaciclib enhanced human CAR-T cell cytotoxicity and metabolic fitness while reducing expansion. In vivo, the combination outperformed single agents against retinoblastoma protein (RB)-proficient, trilaciclib-sensitive CD19+ leukemia. However, in an equivalent RB-deficient model, the combination therapy was no more effective than CAR-T cells alone, suggesting that enhanced CAR-T cell function may be offset by reduced expansion. In contrast, in solid cancer models the combination was consistently more efficacious than either monotherapy. Notably, combination effects were most pronounced in immunocompetent mouse models, including a model with poor sensitivity to trilaciclib as a monotherapy. Mechanistically, CDK4/6 inhibition reduced tumor-infiltrating T-regulatory cells while enhancing CD8+ CAR-T cell persistence, tumor trafficking, and cytotoxic function within the tumor. Together, these findings suggest that trilaciclib and CAR-T cell therapy may be an effective combinatorial treatment for solid cancers.

Author Info: (1) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VI

Author Info: (1) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia. Electronic address: emily.lelliott@petermac.org. (2) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia. (3) Cancer Biology and Therapeutics Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia. (4) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia. (5) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia. (6) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia. (7) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia. (8) Cancer Biology and Therapeutics Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia. (9) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia. (10) Cancer Evolution and Metastasis Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia. (11) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia. (12) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia. (13) Cancer Evolution and Metastasis Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia. (14) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia. (15) Cancer Biology and Therapeutics Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia. Electronic address: shom.goel@petermac.org. (16) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia. Electronic address: jane.oliaro@petermac.org.

Citation: Mol Ther 2026 Jul 1 34:4021-4034 Epub03/24/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41883164

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An in vivo CRISPR screen unveils promising target genes to improve CAR-T cell efficacy in a solid tumor model Spotlight

(1) Fumagalli M (2) An D (3) Simula L (4) Combe C (5) Aziez L (6) Simoni Y (7) Alves-Guerra MC (8) Valentini A (9) Marchais M (10) Vermare A (11) Moraly J (12) Manni S (13) Quadraccia MC (14) Quintarelli C (15) De Angelis B (16) Bercovici N (17) Donnadieu E (18) Pendino F

Molecular therapy | Free PMC Article

Fumagalli et al. developed a focused CRISPR-knockout library targeting loss-of-function of 50 relevant genes to screen low-affinity EGFR CAR-T cells in an orthotopic human lung adenocarcinoma (A549) model. In vivo screening identified ZC3H12A, SOCS1, PTPN2, and CDKN2A loss as top hits that enhanced CAR-T persistence and expansion, whereas MED12, PRDM1, or BATF loss impaired long-term efficacy. Targeted validation of ZC3H12A- and PTPN2-deficient CAR-T cells confirmed improved tumor control and survival. Gene-edited CAR-T cells showed versatility and tumor context specificity, and retained iCasp9 suicide switch activity.

Contributed by Shishir Pant

(1) Fumagalli M (2) An D (3) Simula L (4) Combe C (5) Aziez L (6) Simoni Y (7) Alves-Guerra MC (8) Valentini A (9) Marchais M (10) Vermare A (11) Moraly J (12) Manni S (13) Quadraccia MC (14) Quintarelli C (15) De Angelis B (16) Bercovici N (17) Donnadieu E (18) Pendino F

Molecular therapy | Free PMC Article

Fumagalli et al. developed a focused CRISPR-knockout library targeting loss-of-function of 50 relevant genes to screen low-affinity EGFR CAR-T cells in an orthotopic human lung adenocarcinoma (A549) model. In vivo screening identified ZC3H12A, SOCS1, PTPN2, and CDKN2A loss as top hits that enhanced CAR-T persistence and expansion, whereas MED12, PRDM1, or BATF loss impaired long-term efficacy. Targeted validation of ZC3H12A- and PTPN2-deficient CAR-T cells confirmed improved tumor control and survival. Gene-edited CAR-T cells showed versatility and tumor context specificity, and retained iCasp9 suicide switch activity.

Contributed by Shishir Pant

ABSTRACT: CAR-T cell therapies are revolutionizing the treatment of refractory or relapsed hematological malignancies, but many patients do not achieve durable responses, and these therapies remain ineffective against solid tumors. Therapeutic failure is closely associated with a poor persistence of CAR-T cells in patients, highlighting the need to identify strategies promoting in vivo expansion. Although numerous gene-editing strategies have been proposed, comparative studies to identify the most effective ones are still lacking. Here, using a focused CRISPR-knockout library targeting 50 selected gene candidates, we developed a competitive screening that revealed ZC3H12A, SOCS1, PTPN2, and CDKN2A as the most robust targets to improve persistence of EGFR CAR-T cells in human lung tumor-bearing mice. Surprisingly, disruption of other genes previously reported to improve CAR-T cell efficacy in other preclinical models-MED12, PRDM1, and BATF-had a detrimental effect in this context. These results suggest that some gene-editing strategies can yield beneficial, neutral, or even deleterious effects on CAR-T cell persistence, depending on specific conditions. Altogether, these findings highlight the importance of performing context-specific evaluations of genetic modifications to accelerate the clinical translation of the most promising editing strategies for optimizing CAR-T cell therapies.

Author Info: (1) Université Paris Cité, Institut Cochin, INSERM, CNRS, 75014 Paris, France; Equipe Labélisée Ligue Nationale Contre le Cancer, Paris, France; Thèse Financée par la Ligue Nationa

Author Info: (1) Université Paris Cité, Institut Cochin, INSERM, CNRS, 75014 Paris, France; Equipe Labélisée Ligue Nationale Contre le Cancer, Paris, France; Thèse Financée par la Ligue Nationale Contre le Cancer, Paris, France. Electronic address: fumatia97@gmail.com. (2) Université Paris Cité, Institut Cochin, INSERM, CNRS, 75014 Paris, France; Equipe Labélisée Ligue Nationale Contre le Cancer, Paris, France. (3) Université Paris Cité, Institut Cochin, INSERM, CNRS, 75014 Paris, France; Equipe Labélisée Ligue Nationale Contre le Cancer, Paris, France. (4) Université Paris Cité, Institut Cochin, INSERM, CNRS, 75014 Paris, France; Equipe Labélisée Ligue Nationale Contre le Cancer, Paris, France. (5) Université Paris Cité, Institut Cochin, INSERM, CNRS, 75014 Paris, France. (6) Université Paris Cité, Institut Cochin, INSERM, CNRS, 75014 Paris, France. (7) Université Paris Cité, Institut Cochin, INSERM, CNRS, 75014 Paris, France. (8) Technical University of Denmark, 2800 Kongens Lyngby, Denmark. (9) Université Paris Cité, Institut Cochin, INSERM, CNRS, 75014 Paris, France. (10) Université Paris Cité, Institut Cochin, INSERM, CNRS, 75014 Paris, France; Equipe Labélisée Ligue Nationale Contre le Cancer, Paris, France. (11) Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. (12) Department of Onco-Haematology and Cell and Gene Therapy, Bambino Ges Children's Hospital, IRCCS, 00165 Rome, Italy. (13) Department of Onco-Haematology and Cell and Gene Therapy, Bambino Ges Children's Hospital, IRCCS, 00165 Rome, Italy. (14) Department of Onco-Haematology and Cell and Gene Therapy, Bambino Ges Children's Hospital, IRCCS, 00165 Rome, Italy; Department of Clinical Medicine and Surgery, Federico II University of Naples, 80131 Naples, Italy. (15) Department of Onco-Haematology and Cell and Gene Therapy, Bambino Ges Children's Hospital, IRCCS, 00165 Rome, Italy. (16) Université Paris Cité, Institut Cochin, INSERM, CNRS, 75014 Paris, France; Equipe Labélisée Ligue Nationale Contre le Cancer, Paris, France. (17) Université Paris Cité, Institut Cochin, INSERM, CNRS, 75014 Paris, France; Equipe Labélisée Ligue Nationale Contre le Cancer, Paris, France. (18) Université Paris Cité, Institut Cochin, INSERM, CNRS, 75014 Paris, France; Equipe Labélisée Ligue Nationale Contre le Cancer, Paris, France. Electronic address: frederic.pendino@inserm.fr.

Citation: Mol Ther 2026 Jul 1 34:3976-4000 Epub04/04/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41935953

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Addressing Biases in Analysis of Time of Infusion: NCI/SWOG Trial S1404 Among Participants With High-Risk Resectable Melanoma Who Received Adjuvant Anti-PD-1 Therapy Spotlight

(1) Othus M (2) Truong TG (3) Sharon E (4) Kendra K (5) Grossmann K (6) Buchbinder E (7) Khushalani NI (8) Eroglu Z (9) Chandra S (10) Doolittle GC (11) Kirkwood JM (12) Ikeguchi A (13) Mihalcioiu C (14) Cowey CL (15) Reddy SA (16) Johnson DB (17) Taylor M (18) Sondak VK (19) Ribas A (20) Patel SP

JCO oncology practice - Open Access | Free PMC Article

In an analysis of a multi-center trial involving 628 patients with high-risk melanoma receiving adjuvant pembrolizumab, Othus et al. identified optimal time cut-points for the first infusion of 1:18 pm for recurrence-free survival and 3:48 pm for overall survival (OS). These findings, however, did not reach statistical significance regarding patient outcomes. Furthermore, the lack of threshold robustness was demonstrated when shifting the OS cut-point 30 minutes earlier, which yielded a hazard ratio of 0.98. Average infusion times trended earlier over the year, while appointments were on average later for patients living further from the treatment center.

Contributed by Ute Burkhardt

(1) Othus M (2) Truong TG (3) Sharon E (4) Kendra K (5) Grossmann K (6) Buchbinder E (7) Khushalani NI (8) Eroglu Z (9) Chandra S (10) Doolittle GC (11) Kirkwood JM (12) Ikeguchi A (13) Mihalcioiu C (14) Cowey CL (15) Reddy SA (16) Johnson DB (17) Taylor M (18) Sondak VK (19) Ribas A (20) Patel SP

JCO oncology practice - Open Access | Free PMC Article

In an analysis of a multi-center trial involving 628 patients with high-risk melanoma receiving adjuvant pembrolizumab, Othus et al. identified optimal time cut-points for the first infusion of 1:18 pm for recurrence-free survival and 3:48 pm for overall survival (OS). These findings, however, did not reach statistical significance regarding patient outcomes. Furthermore, the lack of threshold robustness was demonstrated when shifting the OS cut-point 30 minutes earlier, which yielded a hazard ratio of 0.98. Average infusion times trended earlier over the year, while appointments were on average later for patients living further from the treatment center.

Contributed by Ute Burkhardt

PURPOSE: Multiple reports have suggested that receiving immunotherapy infusions earlier in the day is associated with improved outcomes, including longer overall survival (OS) and lower toxicity rates. However, the definition of early varies between publications. Reports also fail to account for confounding factors (including distance to infusion center), are subject to survivor bias (analyzing postbaseline factors at baseline), and do not adjust P values for multiple comparisons when evaluating multiple potential thresholds for early versus late time of day of infusion. METHODS: We analyzed a previously reported multicenter clinical trial evaluating pembrolizumab as adjuvant therapy for participants with resectable high-risk melanoma. Standard statistical methodologies that account for potential biasses were used to evaluate the association between time of day of infusion and clinical outcomes. RESULTS: A total of 628 participants received pembrolizumab and had time of first infusion recorded. The median age was 55 years, range, 20-82. Odds of infusion before 11:00 hours increased by 32% over 12 months of therapy (P = .013). Participants living further from their treating institution had later infusion times on average: odds of infusion before 11:00 decreased by 9% for each additional 50 miles (P = .017). The optimal cut point for first infusion time for OS was 15:48 with hazard ratio (HR) = 1.40; changing the cut point by 30 minutes earlier to 15:18 decreased HR to 0.98, indicating lack of robustness of the threshold. No significant association was identified between proportion of early infusions and outcomes in multivariable time-dependent Cox regression models. CONCLUSION: In this multicenter trial of adjuvant pembrolizumab for participants with high-risk melanoma, analyses that account for common sources of bias found no significant association between recurrence-free or OS and time of day of infusion.

Author Info: (1) Division of Public Health, Fred Hutchinson Cancer Center, Seattle WA. (2) Department of Hematology and Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH. (3)

Author Info: (1) Division of Public Health, Fred Hutchinson Cancer Center, Seattle WA. (2) Department of Hematology and Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH. (3) Department of Medicine, Dana Farber Cancer Institute, Boston, MA. Harvard Medical School, Boston, MA. (4) Medical Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH. (5) Medical Oncology, Providence Cancer Institute, Portland, OR. (6) Medical Oncology, Mass General Brigham Cancer Institute, Boston, MA. (7) Department of Cutaneous Oncology, H Lee Moffitt Cancer Center, Tampa, FL. (8) Department of Cutaneous Oncology, H Lee Moffitt Cancer Center, Tampa, FL. (9) Division of Hematology and Oncology, Robert H Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL. (10) Division of Clinical Oncology, University of Kansas Medical Center, Kansas City, KS. (11) Melanoma Program, University of Pittsburgh Medical Center, Hillman Cancer Center, Pittsburgh, PA. (12) Melanoma Medical Oncology, University of Texas, MD Anderson Cancer Center, Houston, TX. (13) Medical Oncology, McGill University Health Centre, Montreal, Canada. (14) Melanoma, Texas Oncology-Baylor Sammons Cancer Center, Dallas, TX. (15) Department of Medical Oncology, Stanford University School of Medicine, Palo Alto, CA. (16) Department of Medicine, Vanderbilt University Medical Center, Nashville, TN. (17) Medical Oncology, Providence Cancer Institute, Portland, OR. (18) Department of Cutaneous Oncology, H Lee Moffitt Cancer Center, Tampa, FL. (19) Department of Medicine, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA. (20) Department of Medicine, University of Colorado-Anschutz Medical Campus, Aurora, CO.

Citation: JCO Oncol Pract 2026 Jun 23 OP2501413 Epub06/23/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42335437

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FLT3L-secreting cDC1 in situ vaccination enhances antitumor immunity and synergizes with PD-1 blockade in murine non-small cell lung cancer Spotlight

(1) Abascal J (2) Dumitras C (3) Tran LM (4) Crosson W (5) Kahangi B (6) Oh M (7) Rennels A (8) Lim RJ (9) Jiang H (10) Reyimjan D (11) Coleman NJ (12) Perez-Reyes E (13) Chin S (14) Krysan K (15) Dubinett SM (16) Liu B (17) Salehi-Rad R

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

Abascal et al. engineered FLT3L-secreting mouse cDC1s that retained APC and phagocytic ability in vitro. In situ vaccination (ISV) with the cDC1s inhibited s.c. tumor growth in multiple syngeneic murine models, including those with driver mutations common in human NSCLC, and increased trafficking of the autologous cDC1s to TdLN and tumor infiltration of T cells. TCGA analysis showed that FLT3L expression in human NSCLC correlated with profiles of B and T cells, activated DCs and HEV-enriched TLS. ISV increased immature TLS formation in the murine TIME and synergized with anti-PD-1 in a NSCLC model to enhance efficacy and induce immune memory.

Contributed by Paula Hochman

(1) Abascal J (2) Dumitras C (3) Tran LM (4) Crosson W (5) Kahangi B (6) Oh M (7) Rennels A (8) Lim RJ (9) Jiang H (10) Reyimjan D (11) Coleman NJ (12) Perez-Reyes E (13) Chin S (14) Krysan K (15) Dubinett SM (16) Liu B (17) Salehi-Rad R

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

Abascal et al. engineered FLT3L-secreting mouse cDC1s that retained APC and phagocytic ability in vitro. In situ vaccination (ISV) with the cDC1s inhibited s.c. tumor growth in multiple syngeneic murine models, including those with driver mutations common in human NSCLC, and increased trafficking of the autologous cDC1s to TdLN and tumor infiltration of T cells. TCGA analysis showed that FLT3L expression in human NSCLC correlated with profiles of B and T cells, activated DCs and HEV-enriched TLS. ISV increased immature TLS formation in the murine TIME and synergized with anti-PD-1 in a NSCLC model to enhance efficacy and induce immune memory.

Contributed by Paula Hochman

BACKGROUND: Non-small cell lung cancer (NSCLC) frequently evades immune surveillance through defective antigen presentation and a suppressive tumor microenvironment (TME), limiting the efficacy of immune checkpoint blockade (ICB). Conventional type 1 dendritic cells (cDC1s) are essential for initiating antitumor CD8(+) T-cell responses; however, their abundance and function are often diminished in NSCLC, contributing to poor outcomes and resistance to immunotherapy. We hypothesized that in situ vaccination (ISV) using gene-modified cDC1s engineered to secrete FMS-like tyrosine kinase 3 ligand (FLT3L) would enhance cDC1 function within the TME, promote antitumor immunity, and improve responses to ICB. METHODS: Syngeneic murine models of NSCLC (Kras(G12D)/P53(-/-)/Lkb1(-/-); Kras(G12D)/P53(-/-) ; and Kras(G12D) ) with varying tumor mutational burden, along with the MC38 model, were used to assess the therapeutic efficacy of FLT3L-cDC1 ISV. Flow cytometry and multiplex immunofluorescence were used to evaluate immune mechanisms of response. To assess translational relevance, immune and tertiary lymphoid structure (TLS) signatures were analyzed in The Cancer Genome Atlas (TCGA) NSCLC datasets, with TLS signatures refined using a retrained xCell2 framework incorporating curated TLS and high endothelial venule (HEV) microdissection datasets. RESULTS: FLT3L-cDC1 ISV remodeled the TME across multiple NSCLC models, inducing T lymphocyte infiltration and expanding cytolytic CD8(+) T cells. FLT3L-cDC1 ISV was associated with increased formation of immature TLS with primary follicle-like features within the TME. TCGA analyses revealed that FLT3L expression correlates with activated DC, T cell, and B cell signatures, as well as HEV-enriched TLS-associated programs. Combination with PD-1 blockade further enhanced the antitumor immunity of FLT3L-cDC1 ISV, resulting in robust local and systemic T-cell activation and the expansion of activated CCR7(+)PD-L1(+) cDC1s and stem-like TCF1(+)PD-1(+) CD8(+) progenitors within the TME. In an LKB1-deficient NSCLC model, FLT3L-cDC1 ISV plus PD-1 blockade induced complete and durable regression in 85% of tumors, leading to long-lasting systemic tumor-specific immune memory, consistent with effective tumor vaccination. CONCLUSIONS: FLT3L-cDC1 ISV represents a rational cytokine-enhanced cellular immunotherapy designed to overcome immunosuppression and restore DC function within the TME, thereby promoting tumor-specific adaptive immune responses and enhancing responsiveness to ICB.

Author Info: (1) Department of Medicine, David Geffen School of Medicine, Los Angeles, California, USA. (2) Department of Medicine, David Geffen School of Medicine, Los Angeles, California, USA

Author Info: (1) Department of Medicine, David Geffen School of Medicine, Los Angeles, California, USA. (2) Department of Medicine, David Geffen School of Medicine, Los Angeles, California, USA. (3) Department of Medicine, David Geffen School of Medicine, Los Angeles, California, USA. VA Greater Los Angeles Healthcare System, Los Angeles, California, USA. (4) Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, Los Angeles, California, USA. (5) Department of Medicine, David Geffen School of Medicine, Los Angeles, California, USA. (6) Department of Medicine, David Geffen School of Medicine, Los Angeles, California, USA. VA Greater Los Angeles Healthcare System, Los Angeles, California, USA. (7) Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, Los Angeles, California, USA. (8) Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, Los Angeles, California, USA. (9) Department of Medicine, David Geffen School of Medicine, Los Angeles, California, USA. (10) UCLA, Los Angeles, California, USA. (11) Department of Medicine, David Geffen School of Medicine, Los Angeles, California, USA. (12) Department of Medicine, David Geffen School of Medicine, Los Angeles, California, USA. (13) Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, Los Angeles, California, USA. (14) Department of Medicine, David Geffen School of Medicine, Los Angeles, California, USA. (15) Department of Medicine, David Geffen School of Medicine, Los Angeles, California, USA. VA Greater Los Angeles Healthcare System, Los Angeles, California, USA. Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, Los Angeles, California, USA. (16) Department of Medicine, David Geffen School of Medicine, Los Angeles, California, USA rsalehirad@mednet.ucla.edu bliu@mednet.ucla.edu. (17) Department of Medicine, David Geffen School of Medicine, Los Angeles, California, USA rsalehirad@mednet.ucla.edu bliu@mednet.ucla.edu. VA Greater Los Angeles Healthcare System, Los Angeles, California, USA.

Citation: J Immunother Cancer 2026 Jun 25 14: Epub06/25/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42350046

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B cell-derived type I interferon sustains T cell functionality upon strong TCR stimulation during chronic infection Spotlight

(1) Gago da Graça C (2) Cao Y (3) Li S (4) Lindemann AF (5) Heyden L (6) Wijesinghe SKM (7) Poch A (8) Nguyen MT (9) Huynh-Anh NT (10) Daum E (11) Chen D (12) Tsui C (13) Rupasinghe E (14) Gantier MP (15) Roers A (16) Thimme R (17) Hofmann M (18) Bedoui S (19) Abdullah Z (20) Schrder J (21) Kallies A (22) Alexandre YO (23) Utzschneider DT

Immunity - Open Access

Graça et al. show that B cells are essential for CD8⁺ T cell effector response during chronic, but not acute, LCMV infection. In chronic infection, splenic B cells sense viruses via TLR7/8-STING pathways and produce IFN-I, which promotes exhausted T cell differentiation and sustain effector function in the spleen, whereas CD8⁺ T cells in the LN or responding to low antigen load were B cell independent. Loss of B cells or IFN-I signaling impaired exhausted T cell cytokine production (‘tolerized-like’). IRF1 integrates IFN-I signals to promote T cell expansion. Chronic human HBV showed a similar antigen-load-dependent effect observed in the murine LCMV model.

Contributed by Shishir Pant

(1) Gago da Graça C (2) Cao Y (3) Li S (4) Lindemann AF (5) Heyden L (6) Wijesinghe SKM (7) Poch A (8) Nguyen MT (9) Huynh-Anh NT (10) Daum E (11) Chen D (12) Tsui C (13) Rupasinghe E (14) Gantier MP (15) Roers A (16) Thimme R (17) Hofmann M (18) Bedoui S (19) Abdullah Z (20) Schrder J (21) Kallies A (22) Alexandre YO (23) Utzschneider DT

Immunity - Open Access

Graça et al. show that B cells are essential for CD8⁺ T cell effector response during chronic, but not acute, LCMV infection. In chronic infection, splenic B cells sense viruses via TLR7/8-STING pathways and produce IFN-I, which promotes exhausted T cell differentiation and sustain effector function in the spleen, whereas CD8⁺ T cells in the LN or responding to low antigen load were B cell independent. Loss of B cells or IFN-I signaling impaired exhausted T cell cytokine production (‘tolerized-like’). IRF1 integrates IFN-I signals to promote T cell expansion. Chronic human HBV showed a similar antigen-load-dependent effect observed in the murine LCMV model.

Contributed by Shishir Pant

ABSTRACT: B cells are highly abundant lymphocytes and central players in humoral immunity. Although T cells are well known to support humoral responses, how B cells influence T cell responses is less understood. Here, we show that B cells are critical for CD8(+) T cell responses to chronic, but not acute, viral infections. In the absence of B cells, T cells responding to chronic infection exhibited severely impaired effector differentiation. This dependency on B cell help was dictated by high antigen loads and strong T cell receptor (TCR) stimulation. Loss of either B cells or interferon-I (IFN-I) signaling led to severe functional deficits in exhausted T cells, implicating B cells as key producers of IFN-I. The IFN-I-dependent T cell response to strong TCR stimulation is mediated, in part, by the transcription factor IRF1. Therefore, during chronic infection, we uncover an important role for B cell-derived IFN-I in modulating T cell responses to strong TCR stimulation.

Author Info: (1) Department of Microbiology and Immunology, the Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia. (2) Department of Microbi

Author Info: (1) Department of Microbiology and Immunology, the Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia. (2) Department of Microbiology and Immunology, the Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia. (3) Department of Microbiology and Immunology, the Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia. (4) Institute of Molecular Medicine and Experimental Immunology, University Hospital Bonn, University of Bonn, Venusberg-Campus 1, 53127 Bonn, Germany. (5) Department of Microbiology and Immunology, the Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia; Institute of Molecular Medicine and Experimental Immunology, University Hospital Bonn, University of Bonn, Venusberg-Campus 1, 53127 Bonn, Germany. (6) Department of Microbiology and Immunology, the Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia. (7) Department of Microbiology and Immunology, the Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia. (8) Department of Microbiology and Immunology, the Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia. (9) Department of Microbiology and Immunology, the Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia. (10) Institute for Immunology, University Hospital Heidelberg, Heidelberg, Germany. (11) Department of Microbiology and Immunology, the Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia. (12) Department of Microbiology and Immunology, the Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia. (13) Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC, Australia; Department of Molecular and Translational Science, Monash University, Clayton, VIC, Australia. (14) Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC, Australia; Department of Molecular and Translational Science, Monash University, Clayton, VIC, Australia. (15) Institute for Immunology, University Hospital Heidelberg, Heidelberg, Germany. (16) Department of Medicine II (Gastroenterology, Hepatology, Endocrinology, and Infectious Diseases), Medical Center, University of Freiburg, Baden-Wrttemberg, Germany. (17) Department of Medicine II (Gastroenterology, Hepatology, Endocrinology, and Infectious Diseases), Medical Center, University of Freiburg, Baden-Wrttemberg, Germany. (18) Department of Microbiology and Immunology, the Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia. (19) Institute of Molecular Medicine and Experimental Immunology, University Hospital Bonn, University of Bonn, Venusberg-Campus 1, 53127 Bonn, Germany. (20) Computational Sciences Initiative (CSI), the Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia. (21) Department of Microbiology and Immunology, the Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia. (22) Department of Microbiology and Immunology, the Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia. Electronic address: yannick.alexandre@unimelb.edu.au. (23) Department of Microbiology and Immunology, the Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia. Electronic address: daniel.utzschneider@unimelb.edu.au.

Citation: Immunity 2026 Jul 2 Epub07/02/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42392074

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IL-2 mutein promotes antigen-specific transplant acceptance in mice through expansion of ST2(+) regulatory T cells Spotlight

(1) Ganchiku Y (2) Ribas GT (3) Lima K (4) Gassen RB (5) Liu K (6) Efe O (7) Griffith JW (8) Luster AD (9) Shriver Z (10) Babcock GJ (11) Rosales IA (12) LeGuern C (13) Borges TJ (14) Riella LV

Nature communications - Open Access | Free PMC Article

Focused on improving transplantation tolerance, Ganchiku et al. evaluated a long-lived, high-affinity receptor binding IL-2 mutein (mIL-2) in multiple solid organ transplantation models. mIL-2 therapy (with transient co-stimulation blockade) significantly improved long-term allograft survival in an Ag-specific manner, which persisted after cessation of treatment. Allograft survival was accompanied by Treg activation, decreased effector T cell activation, and reduced donor specific antibody levels. mIL-2-mediated allograft survival depended on expansion of highly active and suppressive tissue ST2⁺ Tregs and was abrogated in Treg-specific ST2 KO graft recipients.

Contributed by Katherine Turner

(1) Ganchiku Y (2) Ribas GT (3) Lima K (4) Gassen RB (5) Liu K (6) Efe O (7) Griffith JW (8) Luster AD (9) Shriver Z (10) Babcock GJ (11) Rosales IA (12) LeGuern C (13) Borges TJ (14) Riella LV

Nature communications - Open Access | Free PMC Article

Focused on improving transplantation tolerance, Ganchiku et al. evaluated a long-lived, high-affinity receptor binding IL-2 mutein (mIL-2) in multiple solid organ transplantation models. mIL-2 therapy (with transient co-stimulation blockade) significantly improved long-term allograft survival in an Ag-specific manner, which persisted after cessation of treatment. Allograft survival was accompanied by Treg activation, decreased effector T cell activation, and reduced donor specific antibody levels. mIL-2-mediated allograft survival depended on expansion of highly active and suppressive tissue ST2⁺ Tregs and was abrogated in Treg-specific ST2 KO graft recipients.

Contributed by Katherine Turner

ABSTRACT: Although transplantation is the preferred treatment for end-stage organ disease, long-term outcomes are limited by immunosuppressive drug toxicity and immune-mediated injury. Selective in vivo expansion of regulatory T cells (Tregs) using interleukin-2 (IL-2) analogs has emerged as a strategy to induce antigen-specific transplant tolerance with fewer side effects. Herein, we investigate the therapeutic efficacy of an IL-2 mutein molecule (mIL-2) with enhanced receptor specificity and extended half-life in murine models of solid organ transplantation. mIL-2 therapy significantly improves allograft survival in an antigen-specific manner, accompanied by increased Treg activation, decreased effector T cell activation and reduced donor-specific antibody production. Transcriptional profiling reveals expansion of Tregs expressing the suppression of tumorigenicity 2 (ST2) Tregs with heightened activation status and suppressive function. Accordingly, the mIL-2-induced long-term allograft survival is abrogated in Treg-specific ST2 knockout graft recipients, underscoring the critical role of ST2(+) Tregs. These findings identify mIL-2 as an approach to promote long-term transplant tolerance while reducing reliance on conventional immunosuppression.

Author Info: (1) Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA. Department of Gastroenterological Surg

Author Info: (1) Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA. Department of Gastroenterological Surgery I, Graduate School of Medicine, Hokkaido University, Hokkaido, Japan. (2) Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA. (3) Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA. (4) Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA. (5) Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA. (6) Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA. (7) Center for Immunology & Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA. Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. (8) Center for Immunology & Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA. Division of Rheumatology, Allergy & Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. (9) Visterra, Inc., Waltham, MA, USA. (10) Visterra, Inc., Waltham, MA, USA. (11) Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA. (12) Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA. (13) Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA. (14) Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA. LRIELLA@mgh.harvard.edu. Nephrology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. LRIELLA@mgh.harvard.edu.

Citation: Nat Commun 2026 Jun 22 17: Epub06/22/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42331795

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Targeting non-canonical antigens unlocks functional T-cell responses in renal cell carcinoma Spotlight

(1) Wang J (2) Zhu Y (3) He X (4) Yin S (5) He Y (6) Yao P (7) Li J (8) Li X (9) Shi P (10) Qian R (11) Xiao Z (12) Ye X (13) Xi JJ (14) Ye B

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

Using immunopeptidomics and exome and transcriptome sequencing, Wang et al. analyzed 22 RCC samples and identified HLA-I-presented non-canonical tumor-specific antigens (TSA) derived from human endogenous retroviruses and long non-coding RNAs, with some shared across patients. TSA-reactive T cells in the TIME primarily expressed an exhausted phenotype. T cells expressing TSA-reactive TCRs isolated using scRNA seq mediated tumor cell killing/ regression in vitro in RCC patient-derived tumor-like cell clusters cocultured with autologous peripheral lymphocytes and in mouse xenograft models, particularly combined with anti-PD-1.

Contributed by Paula Hochman

(1) Wang J (2) Zhu Y (3) He X (4) Yin S (5) He Y (6) Yao P (7) Li J (8) Li X (9) Shi P (10) Qian R (11) Xiao Z (12) Ye X (13) Xi JJ (14) Ye B

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

Using immunopeptidomics and exome and transcriptome sequencing, Wang et al. analyzed 22 RCC samples and identified HLA-I-presented non-canonical tumor-specific antigens (TSA) derived from human endogenous retroviruses and long non-coding RNAs, with some shared across patients. TSA-reactive T cells in the TIME primarily expressed an exhausted phenotype. T cells expressing TSA-reactive TCRs isolated using scRNA seq mediated tumor cell killing/ regression in vitro in RCC patient-derived tumor-like cell clusters cocultured with autologous peripheral lymphocytes and in mouse xenograft models, particularly combined with anti-PD-1.

Contributed by Paula Hochman

BACKGROUND: Renal cell carcinoma (RCC) frequently exhibits favorable responses to immunotherapy, despite a low tumor mutational burden, suggesting a critical role for non-mutational antigens presented by human leukocyte antigen class I in activating CD8(+) T cells. METHODS: To systematically identify non-canonical tumor-specific antigens, we developed an integrated proteogenomic approach to RCC samples by combining immunopeptidomics with exome and transcriptome sequencing. We subsequently primed and expanded antigen-reactive T cells in vitro, isolated a panel of antigen-specific T-cell receptors, and characterized their functionality. Finally, we investigated the tumor-killing and regression of non-canonical antigen-reactive T cells using patient-derived tumor-like cell clusters and mouse models. RESULTS: We discovered a diverse repertoire of non-canonical tumor-specific antigens derived from human endogenous retroviruses (hERVs) and long non-coding RNAs (lncRNAs), many of which were shared across patients. Single-cell RNA sequencing further revealed that T cells reactive to these antigens were enriched within exhausted subsets in the tumor microenvironment, indicative of persistent antigen-specific stimulation. Functionally, T cells engineered to recognize these non-canonical antigens mediated potent tumor cell killing both in vitro and in vivo. Our findings establish hERV-derived and lncRNA-derived antigens as key drivers of RCC immunogenicity and highlight their strong potential as targets for T-cell-based immunotherapy. CONCLUSIONS: Our work is the first to demonstrate that non-canonical antigens drive immunogenicity in low-mutation RCC, thereby resolving a key question in cancer immunology-how tumors with low mutational burden can provoke robust T-cell responses.

Author Info: (1) State Key Laboratory of Natural and Biomimetic Drugs, Beijing Key Laboratory of Tumor Organoid and Digital Tumor Twin, Department of Biomedical Engineering, College of Future T

Author Info: (1) State Key Laboratory of Natural and Biomimetic Drugs, Beijing Key Laboratory of Tumor Organoid and Digital Tumor Twin, Department of Biomedical Engineering, College of Future Technology, Peking University, Beijing, China. (2) Department of Urology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. (3) State Key Laboratory of Natural and Biomimetic Drugs, Beijing Key Laboratory of Tumor Organoid and Digital Tumor Twin, Department of Biomedical Engineering, College of Future Technology, Peking University, Beijing, China. (4) State Key Laboratory of Natural and Biomimetic Drugs, Beijing Key Laboratory of Tumor Organoid and Digital Tumor Twin, Department of Biomedical Engineering, College of Future Technology, Peking University, Beijing, China. (5) State Key Laboratory of Natural and Biomimetic Drugs, Beijing Key Laboratory of Tumor Organoid and Digital Tumor Twin, Department of Biomedical Engineering, College of Future Technology, Peking University, Beijing, China. (6) Innovative Vaccine and Immunotherapy Research Center, The Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, Zhejiang, China. (7) State Key Laboratory of Natural and Biomimetic Drugs, Beijing Key Laboratory of Tumor Organoid and Digital Tumor Twin, Department of Biomedical Engineering, College of Future Technology, Peking University, Beijing, China. (8) Department of Urology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. (9) State Key Laboratory of Natural and Biomimetic Drugs, Beijing Key Laboratory of Tumor Organoid and Digital Tumor Twin, Department of Biomedical Engineering, College of Future Technology, Peking University, Beijing, China. (10) State Key Laboratory of Natural and Biomimetic Drugs, Beijing Key Laboratory of Tumor Organoid and Digital Tumor Twin, Department of Biomedical Engineering, College of Future Technology, Peking University, Beijing, China. (11) State Key Laboratory of Natural and Biomimetic Drugs, Beijing Key Laboratory of Tumor Organoid and Digital Tumor Twin, Department of Biomedical Engineering, College of Future Technology, Peking University, Beijing, China. (12) Department of Urology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China jzxi@pku.edu.cn bqye@pku.edu.cn yexiongjun@cicams.ac.cn. (13) State Key Laboratory of Natural and Biomimetic Drugs, Beijing Key Laboratory of Tumor Organoid and Digital Tumor Twin, Department of Biomedical Engineering, College of Future Technology, Peking University, Beijing, China jzxi@pku.edu.cn bqye@pku.edu.cn yexiongjun@cicams.ac.cn. (14) State Key Laboratory of Natural and Biomimetic Drugs, Beijing Key Laboratory of Tumor Organoid and Digital Tumor Twin, Department of Biomedical Engineering, College of Future Technology, Peking University, Beijing, China jzxi@pku.edu.cn bqye@pku.edu.cn yexiongjun@cicams.ac.cn.

Citation: J Immunother Cancer 2026 Jun 24 14: Epub06/24/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42342407

Generalizable AI predicts immunotherapy outcomes across cancers and treatments

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Enhancement of ferroptosis in escape variant tumor cells by IFN-γ derived from antigen-specific T cells controls tumor with heterogeneity Spotlight

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Neoadjuvant stereotactic body radiation therapy with durvalumab and oleclumab in ER+HER2- breast cancer: a randomized phase 2 trial Featured

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CDK4/6 inhibition enhances CAR-T cell therapy in solid tumors Spotlight

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An in vivo CRISPR screen unveils promising target genes to improve CAR-T cell efficacy in a solid tumor model Spotlight

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Addressing Biases in Analysis of Time of Infusion: NCI/SWOG Trial S1404 Among Participants With High-Risk Resectable Melanoma Who Received Adjuvant Anti-PD-1 Therapy Spotlight

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FLT3L-secreting cDC1 in situ vaccination enhances antitumor immunity and synergizes with PD-1 blockade in murine non-small cell lung cancer Spotlight

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B cell-derived type I interferon sustains T cell functionality upon strong TCR stimulation during chronic infection Spotlight

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IL-2 mutein promotes antigen-specific transplant acceptance in mice through expansion of ST2(+) regulatory T cells Spotlight

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Targeting non-canonical antigens unlocks functional T-cell responses in renal cell carcinoma Spotlight

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Enhancement of ferroptosis in escape variant tumor cells by IFN-γ derived from antigen-specific T cells controls tumor with heterogeneity
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Neoadjuvant stereotactic body radiation therapy with durvalumab and oleclumab in ER+HER2- breast cancer: a randomized phase 2 trial
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