Remodeling of the immune and stromal cell compartment by PD-1 blockade in mismatch repair-deficient colorectal cancer
Cancer Cell(2023)
摘要
Immune checkpoint inhibitor (ICI) therapy can induce complete responses in mismatch repair-deficient and microsatellite instability-high (d-MMR/MSI-H) colorectal cancers (CRCs). However, the underlying mechanism for pathological complete response (pCR) to immunotherapy has not been completely understood. We utilize single-cell RNA sequencing (scRNA-seq) to investigate the dynamics of immune and stromal cells in 19 patients with d-MMR/MSI-H CRC who received neoadjuvant PD-1 blockade. We found that in tumors with pCR, there is a concerted decrease in CD8(+) Trm-mitotic, CD4(+) Tregs, proinflammatory IL1B(+) Mono and CCL2(+) Fibroblast following treatment, while the proportions of CD8(+) Tem, CD4(+) Th, CD20(+) B, and HLA-DRA(+) Endothelial cells increase. Proinflammatory features in the tumor microenvironment mediate the persistence of residual tumors by modulating CD8(+) T cells and other response-associated immune cell populations. Our study provides valuable resources and biological insights into the mechanism of successful ICI therapy and potential targets for improving treatment efficacy.
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关键词
mismatch repair-deficient,microsatellite instability-high,colorectal cancer,neoadjuvant immunotherapy,PD-1 blockade,single-cell RNA sequencing,tumor immune microenvironment,complete response,stromal cells,immune checkpoint inhibitors
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