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
  • 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: [email protected].
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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