Journal Articles

mRNA vaccine immunity is enhanced by hepatocyte detargeting and not dependent on dendritic cell expression Spotlight 

(1) Marks A (2) Siu S (3) Bianchini F (4) Wang C (5) Lakshmi A (6) Phelan M (7) Zhu A (8) Moon C (9) Morla-Folch J (10) Teunissen AJP (11) Amabile A (12) Baccarini A (13) Merad M (14) Brody JD (15) Dong Y (16) Brown BD

Nature biotechnology

To study how cell type-specific expression on mRNA-encoded proteins influences immunity, Marks and Siu et al. incorporated synthetic microRNA target sites into the mRNA. LNP-delivered mRNA did not need to be directly expressed in professional APCs (pAPCs), and expression in muscle cells was sufficient or stronger in immune response induction than pAPCs. mRNA expression in hepatocytes dampened the CD8+ T cell response and reduced mRNA vaccine control of tumor growth. Silencing mRNA expression in hepatocytes reversed these effects and, when mRNA vaccines were used to expand transferred T cells, reduced liver T cell infiltration and toxicity.

Contributed by Ute Burkhardt

(1) Marks A (2) Siu S (3) Bianchini F (4) Wang C (5) Lakshmi A (6) Phelan M (7) Zhu A (8) Moon C (9) Morla-Folch J (10) Teunissen AJP (11) Amabile A (12) Baccarini A (13) Merad M (14) Brody JD (15) Dong Y (16) Brown BD

Nature biotechnology

To study how cell type-specific expression on mRNA-encoded proteins influences immunity, Marks and Siu et al. incorporated synthetic microRNA target sites into the mRNA. LNP-delivered mRNA did not need to be directly expressed in professional APCs (pAPCs), and expression in muscle cells was sufficient or stronger in immune response induction than pAPCs. mRNA expression in hepatocytes dampened the CD8+ T cell response and reduced mRNA vaccine control of tumor growth. Silencing mRNA expression in hepatocytes reversed these effects and, when mRNA vaccines were used to expand transferred T cells, reduced liver T cell infiltration and toxicity.

Contributed by Ute Burkhardt

ABSTRACT: Proteins encoded by mRNA vaccines can be expressed by a diversity of transfected cell types but how cell-type-specific expression influences immunity is poorly understood. To investigate this, we incorporated synthetic microRNA target sites (miRT) into lipid nanoparticle (LNP)-delivered mRNA vaccines to silence mRNA expression specifically in professional antigen-presenting cells (pAPCs), hepatocytes or myocytes. We found that mRNA expression in pAPCs was dispensable for priming antigen-specific T cells, whereas mRNA expression in myocytes induced similar or stronger immune responses, including for SARS-CoV-2, suggesting that antigen cross-presentation or cross-dressing may be more impactful than direct mRNA expression in pAPCs. In contrast, mRNA expression in hepatocytes suppressed the antigen-specific T cell response, partly through PD1/PDL1. In mice bearing tumor-associated antigen (TAA)-expressing lymphoma cells, miRT-mediated hepatocyte-silenced TAA mRNA vaccine enhanced immune response and reduced tumor burden. Thus, non-pAPC expression shapes immunity to mRNA-encoded protein and inclusion of miRTs can boost or blunt mRNA-LNP immunogenicity.

Author Info: (1) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

Author Info: (1) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (2) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (3) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (4) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (5) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (6) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (7) Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (8) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (9) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Biomedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (10) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Biomedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (11) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (12) Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (13) Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (14) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (15) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (16) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. brian.brown@mssm.edu. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. brian.brown@mssm.edu. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. brian.brown@mssm.edu. Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. brian.brown@mssm.edu.

Citation: Nat Biotechnol 2026 Apr 29 Epub04/29/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42056385

Tags:

Cancer stem cells orchestrate immune evasion through extracellular vesicle-mediated non-canonical signaling pathways Spotlight 

(1) Fan G (2) Jin J (3) Wang J (4) Xu J (5) Ge W (6) Liu S (7) Tang L (8) Reziya W (9) Yang X (10) Li J (11) Ng LG (12) Di L (13) Zheng Y (14) Lan F (15) Chen S (16) Zhang Y (17) Wang X (18) Gao D (19) Liu X (20) Sun H (21) Liu Y (22) Li T (23) Cao Y (24) Tao Z (25) Liu W (26) Wang H

Cancer cell

Fan et al. found that in patient specimens of untreated TNBC, cancer stem cells produced extracellular vesicles enriched for TSPAN8 (EVs-TSPAN8), which interacted with CD103 on T cells via a paracrine signaling mechanism – independent of canonical EV internalization – inducing activation of the LKB1-AMPK-FOXP3 axis. This resulted in enhanced Foxp3 expression, which further increased CD103 expression, resulting in a positive feedback loop that enhanced the formation of pro-tumor CD103+Foxp3+ Tregs. In mouse models of TNBC, neutralizing EVs-TSPAN8+ synergized with anti-PD-1, reducing tumor growth and increasing survival.

Contributed by Lauren Hitchings

(1) Fan G (2) Jin J (3) Wang J (4) Xu J (5) Ge W (6) Liu S (7) Tang L (8) Reziya W (9) Yang X (10) Li J (11) Ng LG (12) Di L (13) Zheng Y (14) Lan F (15) Chen S (16) Zhang Y (17) Wang X (18) Gao D (19) Liu X (20) Sun H (21) Liu Y (22) Li T (23) Cao Y (24) Tao Z (25) Liu W (26) Wang H

Cancer cell

Fan et al. found that in patient specimens of untreated TNBC, cancer stem cells produced extracellular vesicles enriched for TSPAN8 (EVs-TSPAN8), which interacted with CD103 on T cells via a paracrine signaling mechanism – independent of canonical EV internalization – inducing activation of the LKB1-AMPK-FOXP3 axis. This resulted in enhanced Foxp3 expression, which further increased CD103 expression, resulting in a positive feedback loop that enhanced the formation of pro-tumor CD103+Foxp3+ Tregs. In mouse models of TNBC, neutralizing EVs-TSPAN8+ synergized with anti-PD-1, reducing tumor growth and increasing survival.

Contributed by Lauren Hitchings

ABSTRACT: Tumor cells evade anti-tumor immunity by reprogramming tumor microenvironment (TME). Using multiplexed single-cell proteomics to analyze 50 TME-associated proteins across treatment-naive triple-negative breast cancer (TNBC) specimens, we discovered that cancer stem cells (CSCs) drive differentiation and expansion of regulatory T cells (Tregs) via extracellular vesicle (EV)-mediated paracrine signaling. TSPAN8, an integral membrane protein on CSC-derived EVs, interacts with CD103 (integrin αEβ7) on T cells, triggering the formation of LKB1-STRAD-MO25 complex and sequential phosphorylation of LKB1 and AMPKα. This cascade enhances FOXP3 expression, which transactivates CD103, creating a positive feedback loop that drives clonal expansion of immunosuppressive CD103+FOXP3+ Tregs and their associated niche. This EV membrane topology-based mechanism operates independently of canonical EV cargo internalization. Neutralizing EVs-TSPAN8+ with a monoclonal antibody synergized with anti-PD-1 therapy in preclinical models, suggesting a potential approach targeting both CSCs and TME immunosuppression, particularly in TNBC subpopulation with high TSPAN8+ CSCs.

Author Info: (1) State Key Laboratory of Systems Medicine for Cancer, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 20080, China; Precision Research Cent

Author Info: (1) State Key Laboratory of Systems Medicine for Cancer, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 20080, China; Precision Research Center for Refractory Diseases, Shanghai Jiao Tong University Pioneer Research Institute for Molecular and Cell Therapies, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, State Key Laboratory of Innovative Immunotherapy, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 20080, China; Breast and Thyroid Surgery Department, General Surgery Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 20080, China. (2) Department of Medical Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China. (3) Department of Breast, The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, No. 910 Hengshan Road, Shanghai, China. (4) State Key Laboratory of Systems Medicine for Cancer, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 20080, China. (5) Department of Medical Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China. (6) Department of Medical Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China. (7) Department of Oncology, Suzhou Kowloon Hospital, Shanghai Jiao Tong University School of Medicine, Suzhou 21500, China. (8) State Key Laboratory of Systems Medicine for Cancer, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 20080, China. (9) State Key Laboratory of Systems Medicine for Cancer, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 20080, China. (10) State Key Laboratory of Systems Medicine for Cancer, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 20080, China. (11) Research Unit of Immune Regulation and Immune Diseases of Chinese Academy of Medical Sciences, Shanghai Jiao Tong University School of Medicine-Affiliated Renji Hospital, Shanghai 200127, China. (12) Cancer Center, Faculty of Health Science, University of Macau, Macau 999078, China. (13) State Key Laboratory of Genetic Engineering, School of Life Sciences and Human Phenome Institute, Shanghai Cancer Center, Fudan University, Shanghai 200032, China. (14) Shanghai Key Laboratory of Medical Epigenetics, State International Co-laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China. (15) Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China. (16) Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China. (17) Department of Surgery, The Chinese University of Hong Kong Prince of Wales Hospital, Shatin 999077, Hong Kong SAR, China. (18) State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, CAS, Shanghai 200031, China. (19) Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, China. (20) Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China. (21) Shanghai Key Laboratory of Cancer Systems Regulation and Clinical Translation, Jiading District Central Hospital Affiliated Shanghai University of Medicine & Health Sciences, Shanghai 201800, China. (22) Department of Medical Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China. (23) Department of Neurosurgery, Fudan University Shanghai Cancer Center, Shanghai, China. Electronic address: gem23@163.com. (24) Department of Medical Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China. Electronic address: drtaozhh@126.com. (25) Department of Medical Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China. Electronic address: liuwenting1015@163.com. (26) Department of Medical Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; State Key Laboratory of Systems Medicine for Cancer, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 20080, China. Electronic address: whx365@126.com.

Citation: Cancer Cell 2026 May 7 Epub05/07/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42102811

Tags:

Foxp3 drives context-dependent epigenetic programs that define regulatory T cell molecular identity and function Spotlight 

(1) Wei Y (2) Ago H (3) Murakami R (4) Funatsu S (5) Osaki M (6) Nakajima A (7) Hasegawa Y (8) Kawakami R (9) Sakaguchi S (10) Hori S

Science immunology

Wei et al. used Foxp3-transduced conventional T cells as a gain-of-function probe, and identified an endogenous Foxp3+ subset that acquired Treg-like transcriptional, chromatin, and suppressive features, exclusively in vivo. Endogenous Foxp3 induction in vivo required a permissive environment created by reduced AKT-mTOR signaling and Foxp3 engagement with STAT5 and NF-κB at Foxp3 regulatory elements. Foxp3 drove a stepwise chromatin remodeling program at Foxp3-induced open chromatin regions, establishing NFκB-linked core modules shared across Treg subsets, and effector-specific modules co-regulated with AP-1.

Contributed by Shishir Pant

(1) Wei Y (2) Ago H (3) Murakami R (4) Funatsu S (5) Osaki M (6) Nakajima A (7) Hasegawa Y (8) Kawakami R (9) Sakaguchi S (10) Hori S

Science immunology

Wei et al. used Foxp3-transduced conventional T cells as a gain-of-function probe, and identified an endogenous Foxp3+ subset that acquired Treg-like transcriptional, chromatin, and suppressive features, exclusively in vivo. Endogenous Foxp3 induction in vivo required a permissive environment created by reduced AKT-mTOR signaling and Foxp3 engagement with STAT5 and NF-κB at Foxp3 regulatory elements. Foxp3 drove a stepwise chromatin remodeling program at Foxp3-induced open chromatin regions, establishing NFκB-linked core modules shared across Treg subsets, and effector-specific modules co-regulated with AP-1.

Contributed by Shishir Pant

ABSTRACT: Regulatory T cells (T(reg) cells) express the master regulator, Foxp3, and display distinctive epigenetic landscapes ensuring T(reg) cell-specific gene expression and stable suppressive functions, yet Foxp3's contribution to this epigenetic identity remains unclear. Leveraging Foxp3-transduced conventional T cells as a gain-of-function probe in mice, we identified a previously unrecognized subset that acquires endogenous Foxp3 expression, T(reg) cell-like transcriptomic and chromatin features, and suppressive functions exclusively in vivo. These Foxp3-driven features were conserved in T(reg) cells but impaired in Foxp3-mutant T(reg)-like cells, demonstrating a Foxp3 requirement. Induction of endogenous Foxp3 expression in vivo required reduced AKT-mTOR signaling and Foxp3-dependent engagement of STAT5 and nuclear factor _B (NF-_B). Temporal chromatin profiling revealed stepwise Foxp3-driven regulatory programs, including a core program shared across T(reg) cell subsets and effector-specific programs, both associated with NF-_B activity and Foxp3 binding. Thus, Foxp3 integrates cell-intrinsic and environmental contexts to drive epigenetic programs defining T(reg) cell identities and functions, with implications for Foxp3-based therapies.

Author Info: (1) Laboratory of Immunology and Microbiology, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan. (2) Laboratory of Immunology and Microbiology, Graduat

Author Info: (1) Laboratory of Immunology and Microbiology, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan. (2) Laboratory of Immunology and Microbiology, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan. (3) Laboratory of Immunology and Microbiology, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan. Laboratory for Immune Homeostasis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan. (4) Laboratory for Immune Homeostasis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan. (5) Laboratory of Immunology and Microbiology, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan. (6) Laboratory of Immunology and Microbiology, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan. (7) Department of Applied Genomics, Kazusa DNA Research Institute, Chiba 292-0818, Japan. (8) Department of Experimental Pathology, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan. (9) Department of Experimental Pathology, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan. Laboratory of Experimental Immunology, Immunology Frontier Research Center, Osaka University, Osaka, Japan. (10) Laboratory of Immunology and Microbiology, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan. Laboratory for Immune Homeostasis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.

Citation: Sci Immunol 2026 May 11:eaed2111 Epub05/01/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42066061

Tags:

Reprogramming T cell-myeloid crosstalk overcomes immune resistance in colorectal cancer Spotlight 

(1) Mestrallet G (2) Brown M (3) Vaninov N (4) Cho NW (5) Velazquez L (6) Ananthanarayanan A (7) Spitzer M (8) Vabret N (9) Cimen Bozkus C (10) Samstein RM (11) Bhardwaj N

Cell reports. Medicine

Mestrallet et al. focused on resistance mechanisms that limit anti-PD-1 efficacy in colorectal cancer (50% to 100% failure depending on mismatch repair status). Single-cell and spatial analysis of orthotopic and patient-derived CRC models showed anti-PD-1 increased TCR diversity and MHCI/II+ macrophage/DC interactions with T cells. Resistance correlated with immunosuppressive TREM2+ macrophages, multiple checkpoints, and IFITM+ tumors. Targeting TREM2, LAG3, CTLA-4 and PD-1 overcame resistance, and achieved up to 70% or 100% tumor clearance in MMR-proficient or MMR-deficient models, respectively, with immune memory.

Contributed by Katherine Turner

(1) Mestrallet G (2) Brown M (3) Vaninov N (4) Cho NW (5) Velazquez L (6) Ananthanarayanan A (7) Spitzer M (8) Vabret N (9) Cimen Bozkus C (10) Samstein RM (11) Bhardwaj N

Cell reports. Medicine

Mestrallet et al. focused on resistance mechanisms that limit anti-PD-1 efficacy in colorectal cancer (50% to 100% failure depending on mismatch repair status). Single-cell and spatial analysis of orthotopic and patient-derived CRC models showed anti-PD-1 increased TCR diversity and MHCI/II+ macrophage/DC interactions with T cells. Resistance correlated with immunosuppressive TREM2+ macrophages, multiple checkpoints, and IFITM+ tumors. Targeting TREM2, LAG3, CTLA-4 and PD-1 overcame resistance, and achieved up to 70% or 100% tumor clearance in MMR-proficient or MMR-deficient models, respectively, with immune memory.

Contributed by Katherine Turner

ABSTRACT: Colorectal cancer (CRC) accounts for 10% of cancer cases and is the second leading cause of cancer-related deaths. Although anti-PD-1 therapy improves outcomes, 50% of advanced mismatch repair-deficient (MMRd) and most mismatch repair-proficient (MMRp) CRC cases fail to respond. Using orthotopic and patient-derived CRC models with single-cell and spatial analyses, we show that tumor control during anti-PD-1 treatment associates with colocalization of MHC(+) C1Q(+) CXCL9(+) macrophages and TCF(+) PRF1(+) T cells. Resistance correlates with increased TIM3, LAG3, TIGIT, and PD-1 expression on T cells and enrichment of TREM2(+) macrophages in T cell-excluded regions. A combinatorial blockade targeting TREM2, LAG3, CTLA4, and PD-1 induces up to 100% tumor clearance in MMRd and >70% in MMRp models. This strategy promotes immune memory mediated by interactions among MHC(+) macrophages and CD4(+)/CD8(+)/TCF(+) T cells, while reducing immunosuppressive myeloid infiltration and T cell exhaustion, identifying key cellular programs that overcome immune escape in CRC.

Author Info: (1) Division of Hematology and Oncology, Hess Center for Science & Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic ad

Author Info: (1) Division of Hematology and Oncology, Hess Center for Science & Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: guillaume.mestrallet@mssm.edu. (2) Division of Hematology and Oncology, Hess Center for Science & Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. (3) The Marc and Jennifer Lipschultz Precision Immunology Institute, Department of Immunology and Immunotherapy, Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. (4) Department of Radiation Oncology and the Department of Otolaryngology-Head and Neck Surgery, University of California at San Francisco, San Francisco, CA 94143, USA. (5) Division of Hematology and Oncology, Hess Center for Science & Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. (6) Division of Hematology and Oncology, Hess Center for Science & Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. (7) Department of Otolaryngology-Head and Neck Surgery and the Department of Microbiology and Immunology, University of California at San Francisco, San Francisco, CA 94143, USA. (8) The Marc and Jennifer Lipschultz Precision Immunology Institute, Department of Immunology and Immunotherapy, Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. (9) Division of Hematology and Oncology, Hess Center for Science & Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. (10) The Marc and Jennifer Lipschultz Precision Immunology Institute, Department of Immunology and Immunotherapy, Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: robert.samstein@mountsinai.org. (11) Division of Hematology and Oncology, Hess Center for Science & Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: nina.bhardwaj@mssm.edu.

Citation: Cell Rep Med 2026 May 5 102786 Epub05/05/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42092363

Tags:

The circadian gene Dec2 promotes pancreatic cancer progression and dormancy through immune evasion Spotlight 

(1) Wang L (2) Harris CR (3) Dudgeon C (4) Prela O (5) Cazares de Menezes J (6) Shih CH (7) Davidson C (8) Casabianca A (9) De S (10) Narrow W (11) Becker J (12) Grandgenett PM (13) Hollingsworth MA (14) Grem JL (15) Kim M (16) Hong Y (17) Gerber S (18) Vertino PM (19) Gao C (20) Klamer Z (21) Repesh A (22) Hao Y (23) Ryan AT (24) Breitenbach M (25) Bianchi A (26) Datta J (27) Altman BJ (28) Haab B (29) Carpizo DR

Developmental cell

Wang, Harris, and Dudgeon et al. identified the circadian rhythm gene Dec2 as a tumor-intrinsic regulator of dormancy and immune evasion in pancreatic cancer models. Dormant PDAC cells and occult disseminated tumor cells expressed high levels of Dec2, which repressed multiple components of the MHC-I antigen presentation pathway and reduced T cell-mediated cytotoxicity. Tumor surface MHC-I levels oscillated in antiphase to Dec2. Dec2 deletion restored antigen presentation, repolarized the PDAC TME from immune-cold to inflamed, and improved survival in immunocompetent (Ink4a.1 and 6419c5 models), but not immunodeficient mice.

Contributed by Shishir Pant

(1) Wang L (2) Harris CR (3) Dudgeon C (4) Prela O (5) Cazares de Menezes J (6) Shih CH (7) Davidson C (8) Casabianca A (9) De S (10) Narrow W (11) Becker J (12) Grandgenett PM (13) Hollingsworth MA (14) Grem JL (15) Kim M (16) Hong Y (17) Gerber S (18) Vertino PM (19) Gao C (20) Klamer Z (21) Repesh A (22) Hao Y (23) Ryan AT (24) Breitenbach M (25) Bianchi A (26) Datta J (27) Altman BJ (28) Haab B (29) Carpizo DR

Developmental cell

Wang, Harris, and Dudgeon et al. identified the circadian rhythm gene Dec2 as a tumor-intrinsic regulator of dormancy and immune evasion in pancreatic cancer models. Dormant PDAC cells and occult disseminated tumor cells expressed high levels of Dec2, which repressed multiple components of the MHC-I antigen presentation pathway and reduced T cell-mediated cytotoxicity. Tumor surface MHC-I levels oscillated in antiphase to Dec2. Dec2 deletion restored antigen presentation, repolarized the PDAC TME from immune-cold to inflamed, and improved survival in immunocompetent (Ink4a.1 and 6419c5 models), but not immunodeficient mice.

Contributed by Shishir Pant

ABSTRACT: The mechanisms that regulate immune evasion by pancreatic ductal adenocarcinomas (PDACs) remain poorly understood. Using a mouse model of resectable PDAC, we identified an unknown role of the circadian rhythm gene Differentially Expressed in Chondrocytes 2 (Dec2) in regulating tumor progression and dormancy. Deletion of Dec2 from tumor cells substantially increased mouse survival after resection due to an immune-mediated mechanism, as the survival benefit was abrogated under immunodeficient conditions. Dec2 promotes immune evasion by repressing major histocompatibility complex class I (MHC-I)-dependent antigen presentation and by repolarizing the tumor microenvironment from immunologically cold (low T cell infiltration) to hot (elevated T cell infiltration). Dec2 is also a regulator of circadian rhythms, and we found that genes involved in MHC-I antigen presentation and MHC-I surface localization oscillated in a circadian manner, which was lost upon deletion of Dec2 in vitro. We conclude that Dec2 promotes primary PDAC progression and likely metastatic dormancy through immune evasion.

Author Info: (1) Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. (2) Department of Surgery, Division of Surgical O

Author Info: (1) Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. (2) Department of Surgery, Division of Surgical Oncology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. (3) Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA. (4) Department of Surgery, Division of Surgical Oncology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. (5) Department of Biomedical Genetics, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. (6) Department of Biomedical Genetics, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. (7) Department of Biomedical Genetics, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. (8) Department of Surgery, Division of Surgical Oncology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. (9) Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA. (10) Department of Surgery, Division of Surgical Oncology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA; Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA. (11) Dewitt Daughtry Department of Surgery, Division of Surgical Oncology, University of Miami Miller School of Medicine, Miami, FL, USA. (12) Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA. (13) Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA. (14) Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA. (15) Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. (16) Center for Cancer and Cell Biology, Van Andel Institute, Grand Rapids, MI, USA. (17) Center for Cancer and Cell Biology, Van Andel Institute, Grand Rapids, MI, USA. (18) Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA; Department of Biomedical Genetics, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. (19) Center for Advanced Research Technologies, University of Rochester Medical Center, Rochester, NY, USA. (20) Center for Cancer and Cell Biology, Van Andel Institute, Grand Rapids, MI, USA. (21) Center for Cancer and Cell Biology, Van Andel Institute, Grand Rapids, MI, USA. (22) Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. (23) Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. (24) Department of Surgery, Division of Surgical Oncology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. (25) Dewitt Daughtry Department of Surgery, Division of Surgical Oncology, University of Miami Miller School of Medicine, Miami, FL, USA. (26) Dewitt Daughtry Department of Surgery, Division of Surgical Oncology, University of Miami Miller School of Medicine, Miami, FL, USA. (27) Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA; Department of Biomedical Genetics, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. (28) Center for Cancer and Cell Biology, Van Andel Institute, Grand Rapids, MI, USA. (29) Department of Surgery, Division of Surgical Oncology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA; Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA; Department of Biomedical Genetics, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. Electronic address: darren_carpizo@urmc.rochester.edu.

Citation: Dev Cell 2026 Apr 28 Epub04/28/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42055006

Tags:

Selective depletion of virus-specific CD8 T cells from the liver after PD-1 therapy with Fc-intact antibody during chronic infection Spotlight 

(1) Hashimoto M (2) Nasti TH (3) Jin HT (4) Bu M (5) Araki K (6) Lee J (7) Valanparambil RM (8) Akhtar A (9) Khan MA (10) Peng Z (11) Hu Y (12) McManus DT (13) Bahhar I (14) Wieland A (15) Davis CW (16) Ramalingam SS (17) Sharpe AH (18) Ravetch JV (19) Freeman GJ (20) Ahmed R

Proceedings of the National Academy of Sciences of the United States of America | Free PMC Article

Hashimoto et al. demonstrated that the Fc region of species-matched mouse anti-mouse PD-1 antibodies engaged with activating FcγRIII and triggered phagocytosis of LCMV-specific CD8+ T cells in the context of chronic infection. T cell depletion occurred preferentially in the liver, and impaired viral control in this organ. The effect was not limited to a specific antibody clone or IgG subclass, and was affected by mutations in the Fc region (no binding to FcγR) or afucosylation (enhanced FcγR affinity), and the presence of immune complexes. In a CT26 tumor model, the Fc-wild-type antibody depleted intratumoral PD1+ tumor-specific CD8+ T cells and accelerated tumor growth.

Contributed by Ute Burkhardt

(1) Hashimoto M (2) Nasti TH (3) Jin HT (4) Bu M (5) Araki K (6) Lee J (7) Valanparambil RM (8) Akhtar A (9) Khan MA (10) Peng Z (11) Hu Y (12) McManus DT (13) Bahhar I (14) Wieland A (15) Davis CW (16) Ramalingam SS (17) Sharpe AH (18) Ravetch JV (19) Freeman GJ (20) Ahmed R

Proceedings of the National Academy of Sciences of the United States of America | Free PMC Article

Hashimoto et al. demonstrated that the Fc region of species-matched mouse anti-mouse PD-1 antibodies engaged with activating FcγRIII and triggered phagocytosis of LCMV-specific CD8+ T cells in the context of chronic infection. T cell depletion occurred preferentially in the liver, and impaired viral control in this organ. The effect was not limited to a specific antibody clone or IgG subclass, and was affected by mutations in the Fc region (no binding to FcγR) or afucosylation (enhanced FcγR affinity), and the presence of immune complexes. In a CT26 tumor model, the Fc-wild-type antibody depleted intratumoral PD1+ tumor-specific CD8+ T cells and accelerated tumor growth.

Contributed by Ute Burkhardt

ABSTRACT: Anti-programmed cell death 1 (PD-1) antibody therapy is now widely used in various cancers. However, the role of the antibody Fc region in PD-1 directed immunotherapy is not well understood. Preclinical studies commonly use species-mismatched rat anti-mouse antibodies, which may not accurately reflect antibody-Fc gamma receptor (Fc_R) interactions. Here, we used mouse anti-mouse PD-1 antibodies to investigate how the Fc region influences therapeutic efficacy for enhancing CD8 T cell responses using mouse models of chronic lymphocytic choriomeningitis virus infection and CT26 tumors. Treatment with these mouse anti-mouse PD-1 antibodies caused preferential depletion of PD-1+ virus-specific CD8 T cells in the liver, resulting in increased viral titers. These effects of mouse anti-PD-1 antibodies were Fc dependent since mutating the Fc region to block Fc_R interaction prevented PD-1+ CD8 T cell depletion and resulted in effective immunotherapy. Using mice lacking activating Fc_R III or inhibitory Fc_R IIb, we found that depletion of PD-1+ CD8 T cells was mediated via activating Fc_R III. Furthermore, we determined that phagocytic cells, not natural killer cells, were the in vivo effectors that mediated depletion of PD-1+ CD8 T cells. Similar depletion of tumor-specific CD8 T cells and reduced tumor control were observed in the CT26 model with Fc-intact mouse anti-mouse PD-1 treatment. These findings highlight potential negative effects of Fc-functional anti-PD-1 antibodies in therapies for liver cancer, liver metastases, and chronic hepatotropic viral infections. Conversely, Fc_R-mediated depletion could benefit "agonistic" anti-PD-1 antibodies for treatment of autoimmunity. Our research emphasizes the importance of Fc region in tailoring PD-1 therapies for diverse clinical applications.

Author Info: (1) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322.

Author Info: (1) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322. (2) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322. (3) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322. CHA Biotech, CHA Bio Complex, Seongnam-si, Gyeonggi-do 13488, Republic of Korea. (4) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215. Department of Medicine, Harvard Medical School, Boston, MA 02115. Medical Scientist Training Program, UCSF Graduate Division, School of Medicine, University of California, San Francisco, CA 94143. (5) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322. Division of Infectious Diseases, Center for Inflammation and Tolerance, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229. Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229. (6) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322. Viral Immunology Laboratory, Institut Pasteur Korea, Seongnam 13488, Republic of Korea. (7) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322. (8) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322. (9) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322. Immunology Laboratory, Department of Biomedical Engineering, Indian Institute of Technology Ropar, Rupnagar 140001, India. (10) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322. (11) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322. (12) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322. (13) Department of Otolaryngology, Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer Center, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH 43210. (14) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322. Department of Otolaryngology, Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer Center, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH 43210. (15) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322. (16) Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322. Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA 30322. (17) Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA Gene Lay Institute of Immunology and Inflammation of Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA (18) Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, NY 10065. (19) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215. Department of Medicine, Harvard Medical School, Boston, MA 02115. (20) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322. Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA 30322.

Citation: Proc Natl Acad Sci U S A 2026 Apr 14 123:e2427192123 Epub04/08/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41950082

Tags:

Intratumoral Treg cell ablation elicits NK cell-mediated control of CD8 T cell-resistant tumors

Featured  

(1) Zhang C (2) Chien C (3) Jurgaityt_ E (4) Sakiyama K (5) Bockman A (6) Jo Y (7) Lee S (8) Silveria S (9) Andrews E (10) Mende A (11) Zhang L (12) Garcia KC (13) Wagner A (14) DuPage M (15) Raulet D

Science immunology

Zhang et al. found that intratumoral depletion of Tregs elicited potent antitumor NK cell responses that controlled MHC-I-deficient and even MHC-I-proficient cancers expressing sufficient NKG2D ligands. This effect was dependent on cDC2-mediated activation of CD4+ T cells and their subsequent production of IL-2, which directly enhanced NK cell activation and cytotoxic potential. Antibody-mediated depletion of intratumoral Tregs or administration of exogenous IL-2 had similar effects.

(1) Zhang C (2) Chien C (3) Jurgaityt_ E (4) Sakiyama K (5) Bockman A (6) Jo Y (7) Lee S (8) Silveria S (9) Andrews E (10) Mende A (11) Zhang L (12) Garcia KC (13) Wagner A (14) DuPage M (15) Raulet D

Science immunology

Zhang et al. found that intratumoral depletion of Tregs elicited potent antitumor NK cell responses that controlled MHC-I-deficient and even MHC-I-proficient cancers expressing sufficient NKG2D ligands. This effect was dependent on cDC2-mediated activation of CD4+ T cells and their subsequent production of IL-2, which directly enhanced NK cell activation and cytotoxic potential. Antibody-mediated depletion of intratumoral Tregs or administration of exogenous IL-2 had similar effects.

ABSTRACT: Cancer cells frequently lose major histocompatibility complex class I (MHC I) to evade CD8 T cell recognition. Natural killer (NK) cells are poised to target MHC I-deficient cancer cells, but MHC I loss alone is often insufficient to unleash fully effective NK cell responses. Here, we show that selective intratumoral (IT) ablation of regulatory T cells (T(reg) cells) elicited potent antitumor NK cell responses that controlled MHC I-deficient and even MHC I(+) cancers that expressed NKG2D ligands. T(reg) cells controlled the activation, maturation, and antitumor cytotoxic activity of NK cells within the tumor microenvironment. Mechanistically, depletion of IT-T(reg) cells relieved the inhibition of cDC2-dependent induction of IL-2 production by conventional CD4 T cells that was necessary for NK cell activation. Systemically administered antibodies that selectively depleted IT-T(reg) cells similarly empowered NK cell-dependent tumor control. These findings expand the breadth of T(reg) cell-mediated cancer immunosuppression to encompass antitumor NK cells and suggest that therapeutic targeting of T(reg) cells in tumors can control CD8 T cell-resistant cancers.

Author Info: (1) Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA. (2) Department of Electric

Author Info: (1) Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA. (2) Department of Electrical Engineering and Computer Sciences, University of California, Berkeley, Berkeley, CA 94720, USA. Center for Computational Biology, University of California, Berkeley, Berkeley, CA 94720, USA. (3) Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA. (4) Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA. (5) Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA. (6) Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA. (7) Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA. (8) Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA. (9) Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA. (10) Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA. (11) Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA. (12) Department of Molecular and Cellular Physiology and Howard Hughes Medical Institute, Stanford University School of Medicine, Palo Alto, CA 94305, USA. (13) Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA. Department of Electrical Engineering and Computer Sciences, University of California, Berkeley, Berkeley, CA 94720, USA. Center for Computational Biology, University of California, Berkeley, Berkeley, CA 94720, USA. (14) Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA. (15) Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.

Citation: Sci Immunol 2026 Apr 10 11:eadx4411 Epub04/10/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41961946

Tags:

Identification of cycling regulatory T cell precursors as conductors of immune escape during breast carcinoma progression Spotlight 

(1) Bui TM (2) Jimenez ER (3) Li Z (4) Foidart P (5) Puleo J (6) Yan P (7) Jhaveri A (8) Yang L (9) Nishida J (10) Seehawer M (11) Cai X (12) Parker KA (13) Qin X (14) Sumer OE (15) Huang XY (16) Patel A (17) Dillon D (18) McDonnell CH 3rd (19) Rowberry R (20) Jhajj S (21) Baker C (22) Brown DD (23) Strand SH (24) Marks JR (25) Colditz GA (26) Park SY (27) Lee AV (28) Angelo M (29) McAuliffe PF (30) Bobolis K (31) West R (32) Dranoff G (33) Hwang ES (34) Cristea S (35) Polyak K

Cancer cell

Using single-cell and spatial transcriptomics in human and rat models, Bui et al. mapped immune remodeling of normal breast, pre-malignant (DCIS) , and invasive (IBC) breast cancer and identified a proliferative FOXP3int MKI67hi cycling Treg (cycTreg) subset. CycTregs emerged at the DCIS-IBC junction, expanded in IBC, and predicted CD8+ infiltration, TCR diversity, disease-specific survival, and DCIS recurrence. CycTreg abundance correlated with CLEC10A+ cDC2s, high HLA class II, and IL-33-producing CAFs. OX40 agonism plus anti-PD-L1 or IL-33 blockade reduced cycTreg, remodeled CAF states, and restored antitumor immunosurveillance.

Contributed by Shishir Pant

(1) Bui TM (2) Jimenez ER (3) Li Z (4) Foidart P (5) Puleo J (6) Yan P (7) Jhaveri A (8) Yang L (9) Nishida J (10) Seehawer M (11) Cai X (12) Parker KA (13) Qin X (14) Sumer OE (15) Huang XY (16) Patel A (17) Dillon D (18) McDonnell CH 3rd (19) Rowberry R (20) Jhajj S (21) Baker C (22) Brown DD (23) Strand SH (24) Marks JR (25) Colditz GA (26) Park SY (27) Lee AV (28) Angelo M (29) McAuliffe PF (30) Bobolis K (31) West R (32) Dranoff G (33) Hwang ES (34) Cristea S (35) Polyak K

Cancer cell

Using single-cell and spatial transcriptomics in human and rat models, Bui et al. mapped immune remodeling of normal breast, pre-malignant (DCIS) , and invasive (IBC) breast cancer and identified a proliferative FOXP3int MKI67hi cycling Treg (cycTreg) subset. CycTregs emerged at the DCIS-IBC junction, expanded in IBC, and predicted CD8+ infiltration, TCR diversity, disease-specific survival, and DCIS recurrence. CycTreg abundance correlated with CLEC10A+ cDC2s, high HLA class II, and IL-33-producing CAFs. OX40 agonism plus anti-PD-L1 or IL-33 blockade reduced cycTreg, remodeled CAF states, and restored antitumor immunosurveillance.

Contributed by Shishir Pant

ABSTRACT: Immune escape during the ductal carcinoma in situ (DCIS)-to-invasive breast cancer (IBC) transition shapes tumor evolution. Through transcriptomic mapping of the immune landscapes of normal breast, DCIS, and IBC from large patient cohorts, we identified T and myeloid cells as the primary distinguishing features between DCIS and IBC. We discovered cycling regulatory T cells (cycTreg) as an orchestrator of immunosuppression in IBC. cycTreg frequency predicts cytotoxic CD8(+), TCR diversity, disease-specific survival in IBC, and recurrence in DCIS. In a rat model of breast cancer, we demonstrated that cycTreg act as precursors to mature Treg and are inducible by tumor-localized type 2 dendritic cells. Profiling of tumors subjected to OX40 and PD-L1 therapies revealed an IL-33-mediated fibroblast-cycTreg signaling loop, the disruption of which enhances intratumoral antigen-experienced CD8(+) effectors and systemic immunosurveillance. Our study defines cycTreg as critical inducers of immune escape and promising immuno-oncology targets in breast cancer.

Author Info: (1) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of

Author Info: (1) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. (2) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. (3) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. (4) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. (5) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. (6) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. (7) Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA. (8) Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA. (9) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. (10) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. (11) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. (12) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. (13) Duke Cancer Institute, Duke University School of Medicine, Durham, NC 27705, USA. (14) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (15) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (16) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA. (17) Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA. (18) Sutter Institute for Medical Research, Roseville, CA 95661, USA. (19) Sutter Institute for Medical Research, Roseville, CA 95661, USA. (20) Sutter Institute for Medical Research, Roseville, CA 95661, USA. (21) Sutter Institute for Medical Research, Roseville, CA 95661, USA. (22) Institute for Precision Medicine, University of Pittsburgh, Pittsburgh, PA 15260, USA. (23) Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA. (24) Department of Surgery, Duke University School of Medicine, Durham, NC 27708, USA. (25) Department of Surgery, Washington University School of Medicine, St. Louis, MO 63108, USA. (26) Department of Pathology, Seoul National University Bundang Hospital, Seongnam, Gyeonggi, Republic of Korea. (27) Institute for Precision Medicine, University of Pittsburgh, Pittsburgh, PA 15260, USA; UPMC Hillman Cancer Center, Pittsburgh, PA 15213, USA. (28) Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA. (29) UPMC Hillman Cancer Center, Pittsburgh, PA 15213, USA. (30) Sutter Institute for Medical Research, Roseville, CA 95661, USA. (31) Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA. (32) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (33) Department of Surgery, Duke University School of Medicine, Durham, NC 27708, USA. (34) Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA. (35) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. Electronic address: kornelia_polyak@dfci.harvard.edu.

Citation: Cancer Cell 2026 Apr 16 Epub04/16/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41997138

Tags:

Agonistic anti-CD40 antibody treatment converts resident regulatory T cells into activated type 1 effectors within the tumor microenvironment Featured  

(1) Maltez VI (2) Arora C (3) Gribbin KP (4) Caruso B (5) Haerr ME (6) Sor R (7) Lian Q (8) Blise KE (9) Sivagnanam S (10) Sears RC (11) Coussens LM (12) Vonderheide RH (13) Germain RN (14) Byrne KT

Immunity

Maltez et al. reported that in combination with anti-PD-1 and anti-CTLA-4, treatment with agonist anti-CD40 induced spatial reorganization of Tregs within PDAC tumor microenvironments, and supported the conversion of conventional Tregs into “ExTregs”. These effects were dependent on cDC1s through Cxcl9/Cxcr3-mediated recruitment, IFNγ and IL-12 stimulation, and direct TCR–MHC-II interactions with Tregs in the tumor periphery. In Tregs, these interactions activated nuclear translocation of NFAT1, leading to Foxp3 loss and acquisition of Th1-like features, including Tbet and IFNγ expression. Observations in patient samples were consistent with this pattern, and loss of Tregs was associated with longer disease-free survival.

(1) Maltez VI (2) Arora C (3) Gribbin KP (4) Caruso B (5) Haerr ME (6) Sor R (7) Lian Q (8) Blise KE (9) Sivagnanam S (10) Sears RC (11) Coussens LM (12) Vonderheide RH (13) Germain RN (14) Byrne KT

Immunity

Maltez et al. reported that in combination with anti-PD-1 and anti-CTLA-4, treatment with agonist anti-CD40 induced spatial reorganization of Tregs within PDAC tumor microenvironments, and supported the conversion of conventional Tregs into “ExTregs”. These effects were dependent on cDC1s through Cxcl9/Cxcr3-mediated recruitment, IFNγ and IL-12 stimulation, and direct TCR–MHC-II interactions with Tregs in the tumor periphery. In Tregs, these interactions activated nuclear translocation of NFAT1, leading to Foxp3 loss and acquisition of Th1-like features, including Tbet and IFNγ expression. Observations in patient samples were consistent with this pattern, and loss of Tregs was associated with longer disease-free survival.

ABSTRACT: In pancreatic ductal adenocarcinoma (PDAC), agonistic anti-CD40 (αCD40) reduces frequencies of intratumoral regulatory T (Treg) cells despite a lack of CD40 expression on Treg cells. Here, we leveraged spatiotemporal imaging and lineage tracing approaches to examine intratumoral Treg cell fate in a mouse model of PDAC, where immune checkpoint blockade (ICB) (αPD-1 + αCTLA-4) combined with αCD40 controls tumor growth. Intratumoral Foxp3+ Treg cell numbers collapsed upon treatment, dependent on CD40-activated dendritic cells (DCs) and induction of interleukin (IL)-12 and interferon (IFN)-γ. This reduction corresponded with cellular alterations; Treg cells acquired an "ExTreg" phenotype characterized by loss of Foxp3 expression and acquisition of T helper 1 (Th1)-like features (Tbet+IFN-γ+). αCD40 promoted a spatially reorganized tumor microenvironment (TME), with Cxcr3⁺ Treg and ExTreg cells localized to the tumor periphery with Cxcl9-expressing DCs. Through in situ analyses of T cell receptor (TCR) signaling, we found that ExTreg cells had the highest antigen-driven activation among tumor-infiltrating T cells. Reprogramming of intratumoral Treg cells into Th1-like effectors reveals plasticity and an anti-tumor capacity of these cells.

Author Info: (1) Postdoctoral Research Associate Training (PRAT) Program Fellow, NIGMS, NIH, Bethesda, MD, USA; Lymphocyte Biology Section, Laboratory of Immune System Biology, NIAID, NIH, Beth

Author Info: (1) Postdoctoral Research Associate Training (PRAT) Program Fellow, NIGMS, NIH, Bethesda, MD, USA; Lymphocyte Biology Section, Laboratory of Immune System Biology, NIAID, NIH, Bethesda, MD, USA. (2) Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (3) Department of Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, OR, USA. (4) Department of Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, OR, USA. (5) Department of Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, OR, USA; Graduate Program in Biomedical Sciences, Oregon Health and Science University, Portland, OR, USA. (6) Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (7) Lymphocyte Biology Section, Laboratory of Immune System Biology, NIAID, NIH, Bethesda, MD, USA. (8) Department of Biomedical Engineering, Oregon Health and Science University, Portland, OR, USA; The Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA. (9) Department of Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, OR, USA; The Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA. (10) The Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA; Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR, USA; Brenden-Colson Center for Pancreatic Care, Oregon Health and Science University, Portland, OR, USA. (11) Department of Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, OR, USA; The Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA. (12) Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Parker Institute for Cancer Immunotherapy, University of Pennsylvania, Philadelphia, PA, USA. (13) Lymphocyte Biology Section, Laboratory of Immune System Biology, NIAID, NIH, Bethesda, MD, USA; Center for Advanced Tissue Imaging (CAT-I), NIAID and NCI, NIH, Bethesda, MD, USA. Electronic address: rgermain@niaid.nih.gov. (14) Department of Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, OR, USA; The Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA; Brenden-Colson Center for Pancreatic Care, Oregon Health and Science University, Portland, OR, USA; Parker Institute for Cancer Immunotherapy, University of Pennsylvania, Philadelphia, PA, USA. Electronic address: byrneka@ohsu.edu.

Citation: Immunity 2026 Apr 14 59:1058-1074.e7 Epub04/02/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41932343

Tags:

PD-1 antibody-bound progenitor-exhausted CD8+ T cells in lymph nodes boost PD-1-blockade anti-tumor immunity in gastrointestinal cancer

Spotlight 

(1) Nose Y (2) Yasumizu Y (3) Saito T (4) Nakamura Y (5) Jinushi K (6) Fujikawa K (7) Momose K (8) Yamashita K (9) Tanaka K (10) Yamamoto K (11) Makino T (12) Takahashi T (13) Ueyama A (14) Kurokawa Y (15) Sato E (16) Ohkura N (17) Sakaguchi S (18) Wada H (19) Eguchi H (20) Doki Y

Nature communications

Utilizing scRNA/TCRseq, CITEseq, and a novel assay for cell-bound anti-PD-1 to study the dynamics of T cells targeted by anti-PD-1, Nose and Yasumizu et al. first found that abundance of progenitor-exhausted CD8+ T cells (Tpex) in metastasis-free lymph nodes (LNs), but not tumors or metastatic LNs, correlated with better prognosis in patients with anti-PD-1-naive gastric cancer. Anti-PD-1 promoted the proliferation of anti-PD-1high-bound Tpex in LNs, and clonotypes overlapped with intratumoral anti-PD-1-bound exhausted T cells (Tex), suggesting that anti-PD-1high-bound Tpex migrate to the tumor, where they differentiate into Tex.

Contributed by Ute Burkhardt

(1) Nose Y (2) Yasumizu Y (3) Saito T (4) Nakamura Y (5) Jinushi K (6) Fujikawa K (7) Momose K (8) Yamashita K (9) Tanaka K (10) Yamamoto K (11) Makino T (12) Takahashi T (13) Ueyama A (14) Kurokawa Y (15) Sato E (16) Ohkura N (17) Sakaguchi S (18) Wada H (19) Eguchi H (20) Doki Y

Nature communications

Utilizing scRNA/TCRseq, CITEseq, and a novel assay for cell-bound anti-PD-1 to study the dynamics of T cells targeted by anti-PD-1, Nose and Yasumizu et al. first found that abundance of progenitor-exhausted CD8+ T cells (Tpex) in metastasis-free lymph nodes (LNs), but not tumors or metastatic LNs, correlated with better prognosis in patients with anti-PD-1-naive gastric cancer. Anti-PD-1 promoted the proliferation of anti-PD-1high-bound Tpex in LNs, and clonotypes overlapped with intratumoral anti-PD-1-bound exhausted T cells (Tex), suggesting that anti-PD-1high-bound Tpex migrate to the tumor, where they differentiate into Tex.

Contributed by Ute Burkhardt

ABSTRACT: While progenitor-exhausted T cells (Tpex) expressing TCF1 and PD-1 are crucial for the therapeutic effect of immune checkpoint inhibitors (ICIs) with therapeutic anti-PD-1 antibodies (aPD-1), the dynamics of ICI-bound Tpex are not fully understood. In this study, we investigate ICI-bound T cells in detail using combined sequencing analysis at the single-cell level. By analyzing samples from gastrointestinal cancer patients with or without ICI treatment, we find that Tpex are enriched in proximal lymph nodes (LNs) and proliferate at a high rate after ICI treatment. Importantly, aPD-1 high-bound Tpex in LNs share T-cell receptor clonotypes with intratumoral exhausted CD8(+) T cells (Tex), suggesting their migration to tumor sites after ICI treatment. This study thus provides new insights into how ICIs enhance anti-tumor immunity by acting on Tpex in LNs, deepening our understanding of the cellular mechanisms underlying ICI therapy.

Author Info: (1) Department of Gastroenterological Surgery, Graduate School of Medicine, The University of Osaka, Suita, Japan. Department of Clinical Research in Tumor Immunology, Graduate Sch

Author Info: (1) Department of Gastroenterological Surgery, Graduate School of Medicine, The University of Osaka, Suita, Japan. Department of Clinical Research in Tumor Immunology, Graduate School of Medicine, The University of Osaka, Suita, Japan. (2) Experimental Immunology, WPI Immunology Frontier Research Center, The University of Osaka, Suita, Japan. Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives (OTRI), The University of Osaka, Suita, Japan. (3) Department of Gastroenterological Surgery, Graduate School of Medicine, The University of Osaka, Suita, Japan. tsaito@gesurg.med.osaka-u.ac.jp. Department of Clinical Research in Tumor Immunology, Graduate School of Medicine, The University of Osaka, Suita, Japan. tsaito@gesurg.med.osaka-u.ac.jp. (4) Experimental Immunology, WPI Immunology Frontier Research Center, The University of Osaka, Suita, Japan. (5) Department of Gastroenterological Surgery, Graduate School of Medicine, The University of Osaka, Suita, Japan. Department of Clinical Research in Tumor Immunology, Graduate School of Medicine, The University of Osaka, Suita, Japan. (6) Department of Gastroenterological Surgery, Graduate School of Medicine, The University of Osaka, Suita, Japan. Department of Clinical Research in Tumor Immunology, Graduate School of Medicine, The University of Osaka, Suita, Japan. (7) Department of Gastroenterological Surgery, Graduate School of Medicine, The University of Osaka, Suita, Japan. (8) Department of Gastroenterological Surgery, Graduate School of Medicine, The University of Osaka, Suita, Japan. (9) Department of Gastroenterological Surgery, Graduate School of Medicine, The University of Osaka, Suita, Japan. (10) Department of Gastroenterological Surgery, Graduate School of Medicine, The University of Osaka, Suita, Japan. (11) Department of Gastroenterological Surgery, Graduate School of Medicine, The University of Osaka, Suita, Japan. (12) Department of Gastroenterological Surgery, Graduate School of Medicine, The University of Osaka, Suita, Japan. (13) Department of Clinical Research in Tumor Immunology, Graduate School of Medicine, The University of Osaka, Suita, Japan. Pharmaceutical Research Division, Shionogi & Co., Ltd., Toyonaka, Japan. (14) Department of Gastroenterological Surgery, Graduate School of Medicine, The University of Osaka, Suita, Japan. (15) Department of Pathology, Institute of Medical Science (Medical Research Center), Tokyo Medical University, Tokyo, Japan. (16) Experimental Immunology, WPI Immunology Frontier Research Center, The University of Osaka, Suita, Japan. Department of Basic Research in Tumor Immunology, Graduate School of Medicine, The University of Osaka, Osaka, Japan. (17) Experimental Immunology, WPI Immunology Frontier Research Center, The University of Osaka, Suita, Japan. (18) Department of Gastroenterological Surgery, Graduate School of Medicine, The University of Osaka, Suita, Japan. Department of Clinical Research in Tumor Immunology, Graduate School of Medicine, The University of Osaka, Suita, Japan. (19) Department of Gastroenterological Surgery, Graduate School of Medicine, The University of Osaka, Suita, Japan. (20) Department of Gastroenterological Surgery, Graduate School of Medicine, The University of Osaka, Suita, Japan.

Citation: Nat Commun 2026 Apr 8 Epub04/08/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41951588

Tags:
Close Modal

Subscribe to our mailing list

GDPR Marketing Permissions

The Fritsch Foundation/ACIR.org will use the information you provide on this form to be in touch with you and to send you a weekly digest on cance immunotherapy. Click below to confirm that you want to receive the weekly digest by:

You can change your mind at any time by clicking the unsubscribe link in the footer of any email you receive from us, or by contacting us at contact@acir.org. We will treat your information with respect and will never share it with any third-parties. By clicking below, you agree that we may process your information in accordance with these terms.

We use Mailchimp as our marketing platform. By clicking below to subscribe, you acknowledge that your information will be transferred to Mailchimp for processing. Learn more about Mailchimp's privacy practices here.

Close Modal

Small change for you. Big change for us!

This Thanksgiving season, show your support for cancer research by donating your change.

In less than a minute, link your credit card with our partner RoundUp App.

Every purchase you make with that card will be rounded up and the change will be donated to ACIR.

All transactions are securely made through Stripe.