2026-05-06 マウントサイナイ医療システム（MSHS）
＜関連情報＞
- https://www.mountsinai.org/about/newsroom/2026/mount-sinai-study-identifies-new-strategy-to-overcome-immunotherapy-resistance-in-colorectal-cancer
- https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(26)00203-X
T細胞と骨髄系細胞の相互作用を再プログラムすることで、大腸がんにおける免疫抵抗性を克服できる Reprogramming T cell-myeloid crosstalk overcomes immune resistance in colorectal cancer
Guillaume Mestrallet ∙ Matthew Brown ∙ Natalie Vaninov ∙ … ∙ Cansu Cimen Bozkus ∙ Robert M. Samstein S ∙ Nina Bhardwaj
Cell Reports Medicine Published:May 5, 2026
DOI:https://doi.org/10.1016/j.xcrm.2026.102786
Graphical abstract
Highlights
- Anti-PD-1 increases TCR diversity and MHCI/II+ macrophage/DC interactions with T cells
- Resistance involves TREM2+ macrophages, multiple T cell checkpoints, and IFITM+ tumors
- PD-1, LAG3, CTLA-4, and TREM2 blockade prevents MMRd and MMRp tumor progression
- Combination therapy drives macrophage-T cell interactions and immune memory
Summary
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.
