Journal Articles

Spatially confined IL-12 programs CAR-NK through mTORC1 to coordinate antitumor immune networks Spotlight 

(1) Tarannum M (2) Dinh K (3) Stanojevic M (4) Nguyen M (5) Campisi M (6) Maia A (7) Liu F (8) Yang S (9) Birch GC (10) Bobilev E (11) Gillanders I (12) Sheffer M (13) Gupta S (14) Wang J (15) Ganapathy S (16) Michaud DE (17) Dalton GN (18) Chugh S (19) Nguyen QD (20) Paweletz CP (21) Gokhale PC (22) Gao Y (23) Cancelas J (24) Guerriero JL (25) Choueiri TK (26) Barbie DA (27) Aguirre AJ (28) Porter RL (29) Matulonis UA (30) Koreth J (31) Wu CJ (32) Soiffer RJ (33) Ritz J (34) Chen J (35) Romee R

Cancer discovery

Tarannum et al. engineered mesothelin-targeted CAR-NK cells secreting IL-12 tethered to a collagen-binding A3 domain to spatially restrict IL-12 activity within the collagen I/III-rich TIME. IL-12 and CAR signaling converged through Ras-ERK and PI3K pathways to sustain mTORC1 activity, enhancing CAR-NK cell activation, proliferation, and metabolic fitness. Matrix-anchored IL-12 CAR-NK cells also activated bystander NK cells, T cells, and macrophages, without expanding Tregs. In ovarian and pancreatic cancer models, IL-12 CAR-NK cells achieved potent and durable antitumor responses, with limited systemic IL-12 toxicity.

Contributed by Shishir Pant

(1) Tarannum M (2) Dinh K (3) Stanojevic M (4) Nguyen M (5) Campisi M (6) Maia A (7) Liu F (8) Yang S (9) Birch GC (10) Bobilev E (11) Gillanders I (12) Sheffer M (13) Gupta S (14) Wang J (15) Ganapathy S (16) Michaud DE (17) Dalton GN (18) Chugh S (19) Nguyen QD (20) Paweletz CP (21) Gokhale PC (22) Gao Y (23) Cancelas J (24) Guerriero JL (25) Choueiri TK (26) Barbie DA (27) Aguirre AJ (28) Porter RL (29) Matulonis UA (30) Koreth J (31) Wu CJ (32) Soiffer RJ (33) Ritz J (34) Chen J (35) Romee R

Cancer discovery

Tarannum et al. engineered mesothelin-targeted CAR-NK cells secreting IL-12 tethered to a collagen-binding A3 domain to spatially restrict IL-12 activity within the collagen I/III-rich TIME. IL-12 and CAR signaling converged through Ras-ERK and PI3K pathways to sustain mTORC1 activity, enhancing CAR-NK cell activation, proliferation, and metabolic fitness. Matrix-anchored IL-12 CAR-NK cells also activated bystander NK cells, T cells, and macrophages, without expanding Tregs. In ovarian and pancreatic cancer models, IL-12 CAR-NK cells achieved potent and durable antitumor responses, with limited systemic IL-12 toxicity.

Contributed by Shishir Pant

ABSTRACT: Solid tumors evade immunotherapy because of immunosuppressive microenvironments that limit immune cell persistence and function. Although interleukin-12 (IL-12) potently activates antitumor immunity, its clinical use has been constrained by systemic toxicity. Here we engineered a CAR natural killer (NK) cell platform that integrated IL-12 signaling to enhance antitumor immunity. IL-12 signaling synergized with CAR activation to sustain mTORC1 activity through convergent Ras-ERK and PI3K pathways, promoting metabolic fitness, autonomous expansion, and sustained effector function. IL-12 also activated bystander NK cells, T cells, and macrophages to remodel the tumor microenvironment. To improve safety, IL-12 was tethered to a collagen-binding A3-domain, restricting its activity to the extracellular matrix and limiting systemic exposure. In ovarian and pancreatic cancer models, matrix-anchored IL-12 CAR NK cells expanded without exogenous cytokines and achieved durable tumor control. These findings suggest that mTORC1-mediated integration of CAR and cytokine signaling can enhance immune fitness and overcome immunosuppressive tumor microenvironments.

Author Info: (1) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (2) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86

Author Info: (1) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (2) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (3) University of Pittsburgh Pittsburgh, PA United States. ROR: https://ror.org/01an3r305 (4) Dana-Farber Cancer Institute United States. ROR: https://ror.org/02jzgtq86 (5) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (6) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (7) Dana Farber Cancer Institute Boston United States. (8) Dana-Farber Cancer Institute United States. ROR: https://ror.org/02jzgtq86 (9) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (10) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (11) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (12) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (13) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (14) Dana-Farber Brigham Cancer Center Boston, MA United States. ROR: https://ror.org/05rgrbr06 (15) Dana-Farber Cancer Institute Boston United States. ROR: https://ror.org/02jzgtq86 (16) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (17) Dana-Farber Cancer Institute United States. (18) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (19) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (20) Dana-Farber Cancer Institute Boston, Massachusetts United States. ROR: https://ror.org/02jzgtq86 (21) Dana-Farber Cancer Institute Boston United States. ROR: https://ror.org/02jzgtq86 (22) Skyline Therapeutics Cambridge, MA United States. (23) University of Cincinnati Medical Center Cincinnati United States. ROR: https://ror.org/02p72h367 (24) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (25) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (26) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (27) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (28) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (29) Dana-Farber Cancer Institute Boston, Massachusetts United States. ROR: https://ror.org/02jzgtq86 (30) Dana-Farber Cancer Institute Boston United States. ROR: https://ror.org/02jzgtq86 (31) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (32) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (33) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (34) Massachusetts Institute of Technology Cambridge, MA United States. ROR: https://ror.org/042nb2s44 (35) Dana-Farber Cancer Institute, Harvard University Boston, MA United States.

Citation: Cancer Discov 2026 Sep 29 Epub09/29/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42810409

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IL-2/CD25 acts within the tumor microenvironment to reprogram tumor-specific cytotoxic CD8+ T cells while restraining regulatory T-cell accumulation

Spotlight 

(1) LaPorte KM (2) Pöder J (3) Ivanova D (4) Dalzell M (5) Serafini P (6) Villarino AV (7) Malek TR

Journal for immunotherapy of cancer | Free PMC Article

LaPorte et al. show that high-dose mouse IL-2/CD25 fusion protein (mIL-2/CD25) reprograms the CT26 and MC38 tumor microenvironments to favor tumor-specific CD8+ T cells over Tregs. HD mIL-2/CD25 promoted chemokine and inflammatory programs that increased intratumoral CD8+ T cell infiltration, clonal expansion, and differentiation into effector and stem-like states. In contrast, intratumoral Tregs showed impaired IL-2R signaling and effector Treg differentiation, failed to upregulate Foxp3 and CD25, and were prone to cell death. Combination with anti-PD-1 enhanced multiple tumor-specific CD8⁺ T cell effector programs and limited Treg infiltration.

Contributed by Shishir Pant

(1) LaPorte KM (2) Pöder J (3) Ivanova D (4) Dalzell M (5) Serafini P (6) Villarino AV (7) Malek TR

Journal for immunotherapy of cancer | Free PMC Article

LaPorte et al. show that high-dose mouse IL-2/CD25 fusion protein (mIL-2/CD25) reprograms the CT26 and MC38 tumor microenvironments to favor tumor-specific CD8+ T cells over Tregs. HD mIL-2/CD25 promoted chemokine and inflammatory programs that increased intratumoral CD8+ T cell infiltration, clonal expansion, and differentiation into effector and stem-like states. In contrast, intratumoral Tregs showed impaired IL-2R signaling and effector Treg differentiation, failed to upregulate Foxp3 and CD25, and were prone to cell death. Combination with anti-PD-1 enhanced multiple tumor-specific CD8⁺ T cell effector programs and limited Treg infiltration.

Contributed by Shishir Pant

BACKGROUND: Targeting the high-affinity interleukin-2 receptor (IL-2R) on CD8(+) T effector cells elicits potent antitumor responses that are augmented when co-administered with programmed cell death protein 1 (PD-1) blockade. METHODS: Using the mouse IL-2/CD25 fusion protein (mIL-2/CD25) at a high dose (HD) and anti-PD-1 checkpoint blockade, with the CT26 and MC38 colon carcinomas as models, the current study investigated how antitumor responses occurred when regulatory T cells (Tregs) are also a target of HD mIL-2/CD25. Single-cell RNA sequencing (scRNA-seq) and T-cell receptor (TCR) repertoire analysis of tumor-associated immune cells were used to identify how combination therapy reshaped the tumor microenvironment (TME). These data were cross-referenced with published datasets to (1) corroborate TCR specificity and (2) identify how CD8(+) T-cell differentiation is affected by different IL-2/PD-1 strategies. RESULTS: Here, we show that effective antitumor immunity by the combination therapy is a result of HD mIL-2/CD25-dependent reprogramming of CD8(+) tumor-specific T cells that increases their function and supports their expansion within the TME, the latter also shaped by PD-1 blockade. This therapy supports antitumor responses by chemokines and inflammatory cytokines that selectively favor the migration of CD8(+) T cells but not Tregs deep within the tumor. After HD mIL-2/CD25 treatment, Tregs within the TME showed impaired downstream IL-2R signaling, reflected by failed upregulation of forkhead box P3 and CD25, impaired development into effector Tregs, and enhanced cell death, the latter which likely offsets Treg proliferation. Many similarities were noted after direct comparison of these scRNA-seq findings with another study where IL-2 activity was targeted to PD-1(+) CD8(+) T cells. Notably, HD mIL-2/CD25 and anti-PD-1 combination promotes effector and 'stem-like' CD8(+) T-cell subsets, perhaps even to a greater extent than the PD-1-targeted IL-2 strategy. CONCLUSIONS: The efficient differentiation of exhausted CD8(+) T cells into highly functional cells and the resulting potent antitumor responses by HD mIL-2/CD25 plus anti-PD-1 suggest that this approach may augment durable response rates more than currently achieved with checkpoint blockade monotherapy.

Author Info: (1) Department of Microbiology & Immunology, University of Miami Miller School of Medicine, Miami, Florida, USA. Laboratory of Allergic Diseases, National Institute of Allergy and

Author Info: (1) Department of Microbiology & Immunology, University of Miami Miller School of Medicine, Miami, Florida, USA. Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA. (2) Department of Microbiology & Immunology, University of Miami Miller School of Medicine, Miami, Florida, USA. (3) Department of Microbiology & Immunology, University of Miami Miller School of Medicine, Miami, Florida, USA. (4) Department of Microbiology & Immunology, University of Miami Miller School of Medicine, Miami, Florida, USA. (5) Department of Microbiology & Immunology, University of Miami Miller School of Medicine, Miami, Florida, USA. (6) Department of Microbiology & Immunology, University of Miami Miller School of Medicine, Miami, Florida, USA. (7) Department of Microbiology & Immunology, University of Miami Miller School of Medicine, Miami, Florida, USA tmalek@med.miami.edu.

Citation: J Immunother Cancer 2026 Sep 29 14: Epub09/29/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42810810

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Tumor-targeted IL-10 synergizes with IL-2 to enhance antitumor immunity while minimizing immune-related adverse events

Spotlight 

Zhichen Sun (1), Yifei Hu (2), Casey Moore (1,3), Baran D. Sumer (4,5), Tao Wang (6) & Jian Qiao (1,3,5).

Nature communications

By analyzing TGCA data and performing tumor modeling in IL-10R KO mice, Sun et al. showed that concurrent IL-10 and high IL-2 signaling correlated with improved tumor control. Combining intratumoral injections of EGFR+ tumor-targeted Cetuximab-based IL-10 and IL-2 immunocytokines boosted efficacy. Antigen-specific intratumoral CD8+ T cells were reactivated, expanded, less exhausted, and dependent on tumor cell MHC-I expression and intratumoral IL-10R+ DCs. IL-10 signaling in macrophages suppressed high-dose IL-2-induced toxicities. Combination therapy enhanced antitumor responses in ex vivo PDTF models.

Contributed by Paula Hochman

Zhichen Sun (1), Yifei Hu (2), Casey Moore (1,3), Baran D. Sumer (4,5), Tao Wang (6) & Jian Qiao (1,3,5).

Nature communications

By analyzing TGCA data and performing tumor modeling in IL-10R KO mice, Sun et al. showed that concurrent IL-10 and high IL-2 signaling correlated with improved tumor control. Combining intratumoral injections of EGFR+ tumor-targeted Cetuximab-based IL-10 and IL-2 immunocytokines boosted efficacy. Antigen-specific intratumoral CD8+ T cells were reactivated, expanded, less exhausted, and dependent on tumor cell MHC-I expression and intratumoral IL-10R+ DCs. IL-10 signaling in macrophages suppressed high-dose IL-2-induced toxicities. Combination therapy enhanced antitumor responses in ex vivo PDTF models.

Contributed by Paula Hochman

ABSTRACT: Tumor-targeting cytokines have emerged as a promising strategy for cancer immunotherapy, although their mechanisms of action often remain complex. In this study, we develop an approach by combining tumor-targeted IL-10 (CmAb-(IL10)2) with IL-2 (CmAb-IL2) to enhance antitumor immunity while minimizing immune-related adverse events (irAEs). We demonstrate that endogenous IL-10 plays a critical role in IL-2-mediated antitumor effects, and that the combination of CmAb-(IL10)2 and CmAb-IL2 preferentially expands less-exhausted CD8+ T cells within tumors. Mechanistically, we identify that the IL-10/IL-10 receptor (IL-10R) axis in dendritic cells (DCs) is critical for mediating the efficacy of this combination therapy by promoting intratumoral DC function. Furthermore, we show that this combination enhances antitumor immune responses in humanized female mice and ex vivo patient-derived tumor fragments models. Our findings reveal that tumor-targeted IL-10 synergizes with IL-2 to enhance antitumor immunity through the IL-10/IL-10R/DC axis within tumors, while mitigating IL-2-associated irAEs through the IL-10/IL-10R/macrophage axis. This approach offers an IL-10 based strategy to improve the efficacy of immunotherapy while reducing irAEs.

Author Info: 1 - Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA. 2 - Quantitative Biomedical Research Center, Peter O’Donnell Jr. School of Public Hea

Author Info: 1 - Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA. 2 - Quantitative Biomedical Research Center, Peter O’Donnell Jr. School of Public Health, University of Texas Southwestern Medical Center, Dallas, TX, USA. 3 - Immunology Graduate Program, University of Texas Southwestern Medical Center, Dallas, TX, USA. 4 - Department of Otolaryngology, University of Texas Southwestern Medical Center, Dallas, TX, USA. 5 - Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA. 6 - Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. e-mail: Jian.Qiao@UTSouthwestern.edu

Citation: Nat com 2026

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    Inducible IL-12 or IL-18 secreting CAR T cells targeting the glyco-antigen CD176 exhibit potent activity against non-small cell lung cancer in preclinical models Spotlight 

    (1) Malinconico C (2) Weber J (3) Polzien AJ (4) Bonifacius A (5) Umland M (6) Deveuve Q (7) Bargmann T (8) Zimmermann K (9) Gellert J (10) Neubert L (11) DŸbel S (12) Schambach A (13) Braun A (14) Blasczyk R (15) Abken H (16) Hudecek M (17) Dragon AC (18) Eiz-Vesper B

    Cancer immunology research

    Malinconico et al. engineered T cells with both a CAR targeting CD176 (expressed in NSCLC and other tumors), and an inducible cassette encoding either IL-18 or IL-12 that would be expressed following CAR activation of NF-κB. The resulting CD176-iIL18 or CD176-iIL12 TRUCKs showed antigen-dependent secretion of IL-18/IL-12, increased effector molecules, and heightened THP-1 monocyte chemoattraction. They also showed increased cytotoxicity and antitumor activity in vitro, against patient explants, and in vivo, and performed best when both CD4+ and CD8+ T cells were included. TRUCKs producing IL-12 outperformed those producing IL-18, but with more toxicity.

    Contributed by Lauren Hitchings

    (1) Malinconico C (2) Weber J (3) Polzien AJ (4) Bonifacius A (5) Umland M (6) Deveuve Q (7) Bargmann T (8) Zimmermann K (9) Gellert J (10) Neubert L (11) DŸbel S (12) Schambach A (13) Braun A (14) Blasczyk R (15) Abken H (16) Hudecek M (17) Dragon AC (18) Eiz-Vesper B

    Cancer immunology research

    Malinconico et al. engineered T cells with both a CAR targeting CD176 (expressed in NSCLC and other tumors), and an inducible cassette encoding either IL-18 or IL-12 that would be expressed following CAR activation of NF-κB. The resulting CD176-iIL18 or CD176-iIL12 TRUCKs showed antigen-dependent secretion of IL-18/IL-12, increased effector molecules, and heightened THP-1 monocyte chemoattraction. They also showed increased cytotoxicity and antitumor activity in vitro, against patient explants, and in vivo, and performed best when both CD4+ and CD8+ T cells were included. TRUCKs producing IL-12 outperformed those producing IL-18, but with more toxicity.

    Contributed by Lauren Hitchings

    ABSTRACT: To date, non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related deaths worldwide, underscoring the urgent need for new treatment options. The oncofetal carbohydrate CD176 is masked on healthy tissues but is present on a variety of cancer entities and is associated with cancer invasiveness and metastasis. In this study, we employed chimeric antigen receptor T cells (CAR-Ts) directed against CD176 for treatment of NSCLC. CD176-CAR-Ts were optimized with an additional inducible cassette encoding IL-18 (CD176-iIL18-TRUCKs) or IL-12 (CD176-iIL12-TRUCKs) to augment antitumor reactivity through autocrine and paracrine signaling. CD176-iIL18- and CD176-iIL12-TRUCKs eradicate NSCLC cells in a 3D tumor spheroid model and tissue slices derived from lung adenocarcinoma patients more potently than CD176-CAR-Ts. Administration of TRUCKs in a lung carcinoma xenograft mouse model results in partial or complete tumor eradication in all mice treated with CD176-iIL12-TRUCKs and in 50% of mice treated with CD176-iIL18-TRUCKs. This study highlights the potential of CD176 as a CAR-T-cell target and suggest CD176-CAR-Ts armored with IL-18 or IL-12 as promising new therapeutic approach for the treatment of NSCLC and several other CD176-positive cancer entities.

    Author Info: (1) Italian Institute of Technology Napoli Italy. ROR: https://ror.org/042t93s57 (2) University Hospital WŸrzburg WŸrzburg Germany. (3) Hannover Medical School Hannover Germany. (4

    Author Info: (1) Italian Institute of Technology Napoli Italy. ROR: https://ror.org/042t93s57 (2) University Hospital WŸrzburg WŸrzburg Germany. (3) Hannover Medical School Hannover Germany. (4) Medizinische Hochschule Hannover Hannover Germany. ROR: https://ror.org/00f2yqf98 (5) Hannover Medical School Hannover Germany. (6) UniversitŠtsklinikum WŸrzburg WŸrzburg Germany. (7) Fraunhofer Institute for Toxicology and Experimental Medicine Hannover, Lower Saxony Germany. ROR: https://ror.org/02byjcr11 (8) Medizinische Hochschule Hannover Hannover Germany. ROR: https://ror.org/00f2yqf98 (9) Glycotope GmbH Berlin Germany. (10) Medizinische Hochschule Hannover Hannover, Low Saxony Germany. ROR: https://ror.org/00f2yqf98 (11) Technische UniversitŠt Braunschweig Braunschweig Germany. ROR: https://ror.org/010nsgg66 (12) Medizinische Hochschule Hannover Hannover Germany. ROR: https://ror.org/00f2yqf98 (13) Fraunhofer Institute for Toxicology and Experimental Medicine Hannover, Lower Saxony Germany. ROR: https://ror.org/02byjcr11 (14) Medizinische Hochschule Hannover Hannover Germany. ROR: https://ror.org/00f2yqf98 (15) Leibniz Institute for Immunotherapy and Univ Regensberg Regensburg Germany. (16) UniversitŠtsklinikum WŸrzburg WŸrzburg Germany. ROR: https://ror.org/03pvr2g57 (17) Medizinische Hochschule Hannover Hannover Germany. ROR: https://ror.org/00f2yqf98 (18) Medizinische Hochschule Hannover Hannover Germany. ROR: https://ror.org/00f2yqf98

    Citation: Cancer Immunol Res 2026 Sep 22 Epub09/22/2026

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42770707

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    CD4 T cells convert transient responses to KRAS inhibition to durable remissions in pancreatic cancer Featured  

    (1) Qiang L (2) Hoffman MT (3) Chun JH (4) Parent B (5) Hambitzer F (6) Peprah F (7) Kureshi CTS (8) Lim BS (9) Chang E (10) Walsh MJ (11) Tello JG (12) Atajanova T (13) Shin H (14) Perkins C (15) Kureshi R (16) Molina-Aponte Y (17) Dougan JM (18) Zuo C (19) Brais L (20) Clancy TE (21) Cleary JM (22) Hornick JL (23) Huffman BM (24) Mancias JD (25) Molina G (26) Fairweather M (27) Nowak JA (28) Perez KJ (29) Rubinson DA (30) Slater S (31) van Dams R (32) Wang J (33) Wolpin BM (34) Wong KK (35) Singh H (36) Aguirre AJ (37) Baker D (38) Dougan M (39) Dougan SK

    Cell

    Qiang, Hoffman, Chun, et al. investigated immunotherapy combinations with KRAS inhibition in PDAC models. An IL-21 mimic synergized with a KRAS inhibitor, inducing durable antitumor efficacy. Therapy induced responses from IFNγ-producing CD4+ Th1 cells, decreased Tregs, and stimulated macrophage tumor phagocytosis.

    (1) Qiang L (2) Hoffman MT (3) Chun JH (4) Parent B (5) Hambitzer F (6) Peprah F (7) Kureshi CTS (8) Lim BS (9) Chang E (10) Walsh MJ (11) Tello JG (12) Atajanova T (13) Shin H (14) Perkins C (15) Kureshi R (16) Molina-Aponte Y (17) Dougan JM (18) Zuo C (19) Brais L (20) Clancy TE (21) Cleary JM (22) Hornick JL (23) Huffman BM (24) Mancias JD (25) Molina G (26) Fairweather M (27) Nowak JA (28) Perez KJ (29) Rubinson DA (30) Slater S (31) van Dams R (32) Wang J (33) Wolpin BM (34) Wong KK (35) Singh H (36) Aguirre AJ (37) Baker D (38) Dougan M (39) Dougan SK

    Cell

    Qiang, Hoffman, Chun, et al. investigated immunotherapy combinations with KRAS inhibition in PDAC models. An IL-21 mimic synergized with a KRAS inhibitor, inducing durable antitumor efficacy. Therapy induced responses from IFNγ-producing CD4+ Th1 cells, decreased Tregs, and stimulated macrophage tumor phagocytosis.

    ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is refractory to most therapies, including immunotherapies, for which reinvigoration of CD8 T cells through immune checkpoint blockade is insufficient to induce long-term, durable remissions. Direct KRAS inhibitors (KRASi) have shown clinical promise, although acquired resistance is common. We modeled KRASi response and relapse in mice and demonstrated that, unlike chemotherapy or combinations with checkpoint blockade, an interleukin (IL)-21 cytokine mimic (21h10) induced long-term, durable remissions. Its efficacy depends on T helper 1 (Th1)-polarized CD4 T cells, but not on CD8 T cells or tumor cell expression of major histocompatibility complex class I (MHC class I). Specifically, CD4 T cells primed by type 2 conventional dendritic cells (cDC2s) produce interferon _ (IFN-_), which promotes macrophage-mediated phagocytosis of tumor cells. Ex vivo treatment of human PDAC specimens with 21h10 induces IFN-_ production by infiltrating T cells. Thus, IL-21-elicited CD4 T cells exert antitumor activity in mice and potentially in humans, converting transient responses to KRAS inhibition into durable remissions.

    Author Info: (1) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Immunology, Harvard Medical School, Boston, MA 02115, USA. (2)

    Author Info: (1) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Immunology, Harvard Medical School, Boston, MA 02115, USA. (2) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Immunology, Harvard Medical School, Boston, MA 02115, USA. (3) Institute for Protein Design, University of Washington, Seattle, WA 98195, USA; Department of Biochemistry, University of Washington School of Medicine, Seattle, WA 98195, USA. (4) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (5) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (6) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA. (7) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Immunology, Harvard Medical School, Boston, MA 02115, USA. (8) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA. (9) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (10) Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA. (11) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA. (12) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA. (13) Institute for Protein Design, University of Washington, Seattle, WA 98195, USA; Department of Biochemistry, University of Washington School of Medicine, Seattle, WA 98195, USA. (14) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Immunology, Harvard Medical School, Boston, MA 02115, USA. (15) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Immunology, Harvard Medical School, Boston, MA 02115, USA. (16) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Immunology, Harvard Medical School, Boston, MA 02115, USA. (17) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (18) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Immunology, Harvard Medical School, Boston, MA 02115, USA. (19) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (20) Department of Surgery, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. (21) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. (22) Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. (23) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. (24) Department of Radiation Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. (25) Department of Surgery, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. (26) Department of Surgery, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. (27) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. (28) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. (29) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. (30) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. (31) Department of Radiation Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. (32) Department of Surgery, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. (33) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. (34) Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York, NY 10016, USA. (35) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. (36) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. (37) Institute for Protein Design, University of Washington, Seattle, WA 98195, USA; Department of Biochemistry, University of Washington School of Medicine, Seattle, WA 98195, USA; Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA. (38) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. (39) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Immunology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: stephanie_dougan@dfci.harvard.edu.

    Citation: Cell 2026 Sep 23 Epub09/23/2026

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42777708

    Tags:

    Messenger RNA delivery of a dual CD25/CD122 affinity-tuned IL-2 variant prolongs exposure and potentiates antitumor T cell immunity Featured  

    (1) Vormehr M (2) Kranz LM (3) Muik A (4) Fellermeier-Kopf S (5) Beck JD (6) Eisel D (7) Salomon N (8) Lui BG (9) Diekmann J (10) TŸreci (11) Sahin U

    Science advances | Free PMC Article

    Vormehr et al. engineered an IL-2 variant with high affinity for IL-2Rβ and low affinity for IL-2Rα delivered as mRNA encapsulated in lipid nanoparticles. Treatment of murine models showed expansion of tumor-specific CD8+ T cells with no impact on Tregs. Treatment worked synergistically with ICB and vaccination. The safety of clinically relevant doses was demonstrated in non-human primates.

    (1) Vormehr M (2) Kranz LM (3) Muik A (4) Fellermeier-Kopf S (5) Beck JD (6) Eisel D (7) Salomon N (8) Lui BG (9) Diekmann J (10) TŸreci (11) Sahin U

    Science advances | Free PMC Article

    Vormehr et al. engineered an IL-2 variant with high affinity for IL-2Rβ and low affinity for IL-2Rα delivered as mRNA encapsulated in lipid nanoparticles. Treatment of murine models showed expansion of tumor-specific CD8+ T cells with no impact on Tregs. Treatment worked synergistically with ICB and vaccination. The safety of clinically relevant doses was demonstrated in non-human primates.

    ABSTRACT: The therapeutic potential of interleukin-2 (IL-2) in cancer treatment is limited by toxicity challenges, partly due to an unfavorable pharmacokinetic profile and unintended activation of regulatory T (T(reg)) cells alongside the desired activation of CD8(+) effector T cells. To selectively stimulate CD8(+) T cells over T(reg) cells, we engineered an IL-2 variant (IL-2var) with a dual-tuned affinity profile that features reduced binding to IL-2R_ (CD25) and enhanced binding to IL-2R_ (CD122). To optimize its pharmacokinetics and facilitate tumor enrichment, the variant is fused to albumin and delivered as an mRNA encapsulated in a lipid nanoparticle (Alb-IL-2var RNA-LNP), enabling sustained systemic exposure from hepatic production upon intravenous administration. We show that Alb-IL-2var has a favorable pharmacokinetic profile and is tolerated at biologically active doses in immunocompetent mice and cynomolgus monkeys. Selective enhancement of CD8(+) T cell responses over T(reg) cells is demonstrated in vitro in human peripheral blood mononuclear cells and in vivo in mice and cynomolgus monkeys. When combined with an mRNA cancer vaccine in syngeneic subcutaneous mouse tumor models, Alb-IL-2var RNA-LNP stimulates the expansion of tumor-infiltrating and circulating tumor antigen-specific CD8(+) T cells, but not T(reg) cells. In advanced and cold syngeneic tumor models, it enhances the efficacy of radiotherapy, checkpoint inhibitors, and cancer vaccines. Combination with checkpoint inhibitors and vaccine induces profound proinflammatory conversion of cold tumors. These preclinical results validate a rational design approach to overcome the limitations of IL-2 therapy and support the clinical evaluation of Alb-IL-2var RNA-LNP for solid cancers.

    Author Info: (1) BioNTech SE, Mainz, Germany. (2) BioNTech SE, Mainz, Germany. (3) BioNTech SE, Mainz, Germany. (4) BioNTech SE, Mainz, Germany. (5) BioNTech SE, Mainz, Germany. (6) BioNTech SE

    Author Info: (1) BioNTech SE, Mainz, Germany. (2) BioNTech SE, Mainz, Germany. (3) BioNTech SE, Mainz, Germany. (4) BioNTech SE, Mainz, Germany. (5) BioNTech SE, Mainz, Germany. (6) BioNTech SE, Mainz, Germany. (7) TRON gGmbH - Translational Oncology at the University Medical Center of the Johannes Gutenberg University, Mainz, Germany. (8) BioNTech SE, Mainz, Germany. (9) BioNTech SE, Mainz, Germany. (10) BioNTech SE, Mainz, Germany. HI-TRON - Helmholtz Institute for Translational Oncology Mainz (HI-TRON Mainz) of the DKFZ, Mainz, Germany. (11) BioNTech SE, Mainz, Germany.

    Citation: Sci Adv 2026 Sep 4 12:eaeh9215 Epub09/04/2026

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42696566

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    Neutralizing the IL-12/IL-23 p40 subunit prevents immune checkpoint blockade toxicity without compromising antitumor efficacy Spotlight 

    (1) Groeneveldt C (2) Vadgama D (3) Onrust-van Schoonhoven A (4) Whyte D (5) Hofman MM (6) Rozendaal NEM (7) van Nimwegen M (8) Eterman M (9) Dumoulin DW (10) Mathijssen RHJ (11) Joosse A (12) van der Veldt AAM (13) Boon L (14) Doukas M (15) Samsom JN (16) Stadhouders R (17) Dammeijer F (18) Aerts JGJV (19) Joosse ME

    Cancer immunology research

    Groeneveldt et al. investigated mechanisms driving early-stage immune-related adverse events (irAEs) in patients with metastatic melanoma treated with combination ICB (anti-PD-1 and anti-CTLA-4). Proteomic analysis of serum identified an early, significant increase of p40, a subunit of IL-12/I-23, prior to the onset of clinically apparent irAEs, which was not associated with ICB efficacy. In mouse models that mimic irAEs in patients, p40 neutralization prevented ICB-induced toxicity, without compromising antitumor T cell immunity, including the establishment of tumor-specific responses, suggesting distinct mechanisms that can be uncoupled.

    Contributed by Katherine Turner

    (1) Groeneveldt C (2) Vadgama D (3) Onrust-van Schoonhoven A (4) Whyte D (5) Hofman MM (6) Rozendaal NEM (7) van Nimwegen M (8) Eterman M (9) Dumoulin DW (10) Mathijssen RHJ (11) Joosse A (12) van der Veldt AAM (13) Boon L (14) Doukas M (15) Samsom JN (16) Stadhouders R (17) Dammeijer F (18) Aerts JGJV (19) Joosse ME

    Cancer immunology research

    Groeneveldt et al. investigated mechanisms driving early-stage immune-related adverse events (irAEs) in patients with metastatic melanoma treated with combination ICB (anti-PD-1 and anti-CTLA-4). Proteomic analysis of serum identified an early, significant increase of p40, a subunit of IL-12/I-23, prior to the onset of clinically apparent irAEs, which was not associated with ICB efficacy. In mouse models that mimic irAEs in patients, p40 neutralization prevented ICB-induced toxicity, without compromising antitumor T cell immunity, including the establishment of tumor-specific responses, suggesting distinct mechanisms that can be uncoupled.

    Contributed by Katherine Turner

    ABSTRACT: Immune checkpoint blockade (ICB) has markedly improved overall survival in various cancers, but is associated with severe and sometimes fatal immune-related adverse events (irAEs). Current management of irAEs involves discontinuation of ICB therapy and administration of immunosuppressive drugs, such as corticosteroids, which have been associated with decreased antitumor efficacy. Although irAE development is associated with ICB response, it is currently unknown whether their underlying mechanisms are shared or distinct. To identify early and targetable drivers of irAEs, we performed proteomic analyses on the serum of patients with cancer treated with anti-PD-1 and anti-CTLA-4 combination ICB. We identified a significantly increased concentration of p40, a subunit of IL-12/IL-23, shortly after the start of ICB but before the onset of clinically apparent irAEs. Importantly, increased p40 levels were not associated with ICB efficacy. Neutralizing p40 mitigated ICB-induced toxicity in various mouse models without impairing ICB-induced antitumor efficacy. In conclusion, we demonstrated that IL-12/IL-23p40 is a key mediator of ICB-induced toxicity while being redundant for ICB antitumor efficacy. This shows that the mechanisms underlying ICB toxicity and efficacy can be uncoupled and provides a rationale for p40 blockade in clinical trials with ICB treatment to prevent irAEs in patients.

    Author Info: (1) Erasmus MC Rotterdam Netherlands. ROR: https://ror.org/018906e22 (2) Erasmus MC Cancer Institute Rotterdam, South-Holland Netherlands. ROR: https://ror.org/03r4m3349 (3) Erasmu

    Author Info: (1) Erasmus MC Rotterdam Netherlands. ROR: https://ror.org/018906e22 (2) Erasmus MC Cancer Institute Rotterdam, South-Holland Netherlands. ROR: https://ror.org/03r4m3349 (3) Erasmus MC Netherlands. ROR: https://ror.org/018906e22 (4) Cancer Research UK Scotland Institute United Kingdom. ROR: https://ror.org/03pv69j64 (5) Erasmus MC Cancer Institute Rotterdam Netherlands. ROR: https://ror.org/03r4m3349 (6) Erasmus MC Cancer Institute Netherlands. ROR: https://ror.org/03r4m3349 (7) Erasmus MC Rotterdam Rotterdam Netherlands. (8) Erasmus MC Cancer Institute Netherlands. ROR: https://ror.org/03r4m3349 (9) Erasmus MC Rotterdam Rotterdam Netherlands. (10) Erasmus MC Cancer Institute Rotterdam Netherlands. ROR: https://ror.org/03r4m3349 (11) Erasmus MC Cancer Institute Rotterdam Netherlands. ROR: https://ror.org/03r4m3349 (12) Erasmus MC Rotterdam Netherlands. ROR: https://ror.org/018906e22 (13) University of Warsaw Poland. ROR: https://ror.org/039bjqg32 (14) Erasmus MC Rotterdam Netherlands. ROR: https://ror.org/018906e22 (15) Erasmus MC - Sophia Children's Hospital Rotterdam, South Holland Netherlands. ROR: https://ror.org/047afsm11 (16) Erasmus MC Rotterdam Netherlands. ROR: https://ror.org/018906e22 (17) Erasmus MC Rotterdam Rotterdam Netherlands. (18) Erasmus MC Cancer Institute Rotterdam Netherlands. ROR: https://ror.org/03r4m3349 (19) Erasmus MC Cancer Institute Rotterdam Netherlands. ROR: https://ror.org/03r4m3349

    Citation: Cancer Immunol Res 2026 Aug 31 Epub08/31/2026

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42671933

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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 | 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 | 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

    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

    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-WŸrttemberg, Germany. (17) Department of Medicine II (Gastroenterology, Hepatology, Endocrinology, and Infectious Diseases), Medical Center, University of Freiburg, Baden-WŸrttemberg, 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 | 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 | 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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