Deregulated Mucosal Immune Surveillance through Gut-Associated Regulatory T Cells and PD-1+ T Cells in Human Colorectal Cancer

Abstract

Disturbed balance between immune surveillance and tolerance may lead to poor clinical outcomes in some malignancies. In paired analyses of adenocarcinoma and normal mucosa from 142 patients, we found a significant increase of the CD4/CD8 ratio and accumulation of regulatory T cells (Tregs) within the adenocarcinoma. The increased frequency of Tregs correlated with the local infiltration and extension of the tumor. There was concurrent maturation arrest, upregulation of programmed death-1 expression, and functional impairment in CD8 + T cells (CTLs) isolated from the adenocarcinoma. Adenocarcinoma-associated Tregs directly inhibit the function of normal human CTLs in vitro. With histopathological analysis, Foxp3 + Tregs were preferentially located in stroma. Concurrent transcriptome analysis of epithelial cells, stromal cells, and T cell subsets obtained from carcinomatous and normal intestinal samples from patients revealed a distinct gene expression signature in colorectal adenocarcinoma-associated Tregs, with overexpression of CCR1, CCR8, and TNFRSF9, whereas their ligands CCL4 and TNFSF9 were found upregulated in cancerous epithelium. Overexpression of WNT2 and CADM1, associated with carcinogenesis and metastasis, in cancer-associated stromal cells suggests that both cancer cells and stromal cells play important roles in the development and progression of colorectal cancer through the formation of a tumor microenvironment. The identification of CTL anergy by Tregs and the unique gene expression signature of human Tregs and stromal cells in colorectal cancer patients may facilitate the development of new therapeutics against malignancies.

Reconstruction of cell spatial organization from single-cell RNA sequencing data based on ligand-receptor mediated self-assembly

“…According to the spatial organization reconstructed by CSOmap, Texs could be further divided into two subgroups: Texs interacting and not interacting with Tregs. Consistent with a previous report, 39 MKi67 was depleted in Texs interacting with Tregs (Fig. 7f ), suggesting reduced proliferation by Tregs.…”

Reconstruction of cell spatial organization based on ligand-receptor mediated self-assembly

“…According to the spatial organization reconstructed by CSOmap, Texs could be further divided into two subgroups: Texs interacting and not interacting with Tregs. Consistent with a previous report 33 , MKi67 levels were depleted in Texs interacting with Tregs ( Supplementary Fig. 6f), suggesting inhibited proliferation by Tregs.…”

Comprehensive review of targeted therapy for colorectal cancer

“…363,364 Indeed, in paired patient samples from CRC tissues and normal mucosa, increased numbers of Treg cells were observed in the CRC tissues. 365 These PD-1-expressing Treg cells are considered crucial in the immune tolerance and homeostasis of CRC. Moreover, MHC-1-loss-detecting NK cells, which are effective in killing tumors that use downregulation of MHC-1 as a method of immune escape, were found to be dysfunctional in CRC, also partially because of the PD-1/PD-L1 interaction.…”