2. Academic Validation
  3. 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

  • Cancer Cell. 2023 May 9;S1535-6108(23)00137-X. doi: 10.1016/j.ccell.2023.04.011.
Jianxia Li 1,  Cheng Wu 2,  Huabin Hu 1,  Ge Qin 1,  Xueqian Wu 1,  Fan Bai 1,  Jianwei Zhang 1,  Yue Cai 1,  Yan Huang 3,  Chao Wang 3,  Jiaqi Yang 2,  Yizhao Luan 2,  Zehang Jiang 2,  Jiayu Ling 1,  Zehua Wu 1,  Yaoxu Chen 4,  Zhi Xie 2,  Yanhong Deng 5
Affiliations

Affiliations

  • 1 Department of Medical Oncology, Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China.
  • 2 State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510627, China.
  • 3 Department of Pathology, Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China.
  • 4 Medical Affairs, 3D Medicines Inc., Shanghai 201114, China.
  • 5 Department of Medical Oncology, Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China. Electronic address: dengyanh@mail.sysu.edu.cn.
PMID: 37172580 DOI: 10.1016/j.ccell.2023.04.011
Abstract

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.

Keywords

PD-1 blockade; colorectal cancer; complete response; immune checkpoint inhibitors; microsatellite instability-high; mismatch repair-deficient; neoadjuvant immunotherapy; single-cell RNA sequencing; stromal cells; tumor immune microenvironment.

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