Remodeling of the immune and stromal cell compartment by PD-1 blockade in mismatch repair-deficient colorectal cancer

• Published in: Cancer cell 2023-06, Vol.41 (6), p.1152-1169.e7
• Main Authors: Li, Jianxia, Wu, Cheng, Hu, Huabin, Qin, Ge, Wu, Xueqian, Bai, Fan, Zhang, Jianwei, Cai, Yue, Huang, Yan, Wang, Chao, Yang, Jiaqi, Luan, Yizhao, Jiang, Zehang, Ling, Jiayu, Wu, Zehua, Chen, Yaoxu, Xie, Zhi, Deng, Yanhong
• Format: Article
• Language: English
• Subjects: CD8-Positive T-Lymphocytes - pathology; Colonic Neoplasms; colorectal cancer; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; complete response; DNA Mismatch Repair; Endothelial Cells; Humans; immune checkpoint inhibitors; Microsatellite Instability; microsatellite instability-high; mismatch repair-deficient; neoadjuvant immunotherapy; PD-1 blockade; Programmed Cell Death 1 Receptor; single-cell RNA sequencing; stromal cells; tumor immune microenvironment; Tumor Microenvironment
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/j.ccell.2023.04.011

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. [Display omitted] •Immune and stromal cell alterations occur in d-MMR/MSI-H CRC following PD-1 blockade•Changes in the CD8+ T cell cytotoxic and proliferation programs are response-related•ICI decreases CD4+ Tregs and increases CD40+ B cells in complete responsive tumors•Resolution of tumor-promoting inflammation correlates with ICI response Li et al. use scRNA-seq and multiplex immunohistochemistry to investigate the cellular dynamics in patients with d-MMR/MSI-H CRC treated with neoadjuvant toripalimab, revealing immune and stromal features of complete responders and non-complete responders and highlighting the role of inflammatory conditions in regulating the balance between immune clearance and immune escape.