Remodeling of the immune and stromal cell compartment by PD-1 blockade in mismatch repair-deficient colorectal cancer
Remodeling of the immune and stromal cell compartment by PD-1 blockade in mismatch repair-deficient colorectal cancer
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DOI：
10.1016/j.ccell.2023.04.011
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发表时间：
2023-06-12
期刊：
影响因子：
50.3
通讯作者：
Deng, Yanhong
中科院分区：
文献类型：
--
作者：
Li, Jianxia;Wu, Cheng;Deng, Yanhong
免疫检查点抑制剂（ICI）治疗可以诱导错配修复缺陷和微卫星不稳定性高（d-MMR/MSI-H）结直肠癌（CRC）的完全缓解。然而，对免疫治疗的病理完全应答（pCR）的潜在机制尚未完全理解。我们利用单细胞RNA测序（scRNA-seq）研究了19例接受新辅助PD-1阻断的d-MMR/MSI-H CRC患者的免疫和基质细胞动力学。我们发现，在pCR肿瘤中，治疗后CD 8（+）Tem-有丝分裂细胞、CD 4（+）T细胞、促炎性IL 1 B（+）Mono和CCL 2（+）成纤维细胞的比例一致下降，而CD 8（+）Tem、CD 4（+）Th、CD 20（+）B和HLA-β（+）内皮细胞的比例增加。肿瘤微环境中的促炎特征通过调节CD 8（+）T细胞和其他反应相关免疫细胞群介导残留肿瘤的持续存在。我们的研究为成功的ICI治疗机制和改善治疗效果的潜在靶点提供了宝贵的资源和生物学见解。
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.