Coordinated macrophage and T cell interactions mediate response to checkpoint blockade in colorectal cancer
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Mismatch repair deficiency (MMRd), either due to inherited or somatic mutation, is prevalent in colorectal cancer (CRC) and other cancers. While anti-PD-1 therapy is utilized in both local and advanced disease, up to 50% of MMRd CRC fail to respond. Using animal and human models of MMRd, we determined that interactions between MHC+ C1Q+ CXCL9+ macrophages and TCF+ BHLHE40+ PRF1+ T cell subsets are associated with control of MMRd tumor growth, during anti-PD-1 treatment. In contrast, resistance is associated with upregulation of TIM3, LAG3, TIGIT, and PD-1 expression on T cells, and infiltration of the tumor with immunosuppressive TREM2+ macrophages and monocytes. By combining anti-PD-1 with anti-LAG3/CTLA4/TREM2, up to 100% tumor eradication was achieved in MMRd CRC and remarkably, in >70% in MMRp CRC. This study identifies key T cell and macrophage subsets mediating the efficacy of immunotherapy in overcoming immune escape in both MMRd and MMRp CRC settings.
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Highlights
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Anti-PD-1 therapy leads to the accumulation and colocalization of MHCI/II+ C1Q+ CXCL9+ macrophages and DCs with TCF+ CCL5+ T cells that have high TCR diversity.
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Resistance to anti-PD-1 therapy involves multiple T cell checkpoints, TREM2+ macrophages, IL1B+ TREM1+ monocytes and neutrophils, and IFITM+ tumor cells.
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Simultaneous blockade of PD-1, LAG3, CTLA-4 and TREM2 dramatically prevents progression of both MMRd and MMRp tumors.
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Combination therapy completely eliminates tumors by leveraging MHC+ macrophage, CD4+ and CD8+ T cell interactions, facilitating durable anti-tumor effects.
