Reprogramming T cell-myeloid crosstalk overcomes immune resistance in colorectal cancer
(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
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
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
dress: 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
