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

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.