Elevated T Cell Immunoreceptor with Ig and ITIM Domains (TIGIT) Expression and Immune Cell Dysfunction Characterize Complex Proteins Associated With SET1 (COMPASS)-Like Complex Gene-Mutated Pancreatic Ductal Adenocarcinoma (PDAC)

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is highly resistant to immune therapies. Limited biomarkers, such as mismatch repair proteins, have been used to identify those who may respond to immunotherapy. We identified a subset of aggressive PDACs (⁓25%) carrying mutations in the complex of proteins associated with SET1-like complex genes (CLCGs), which can be used as new biomarkers for targeted immunotherapy. In this study, we compared the immune microenvironment of PDACs harboring CLCG mutations with matched wild-type PDACs using multiplex fluorescent immunohistochemistry and computational imaging techniques. We observed that CLCG-mutant PDACs were infiltrated with fewer CD4⁺ T cells and antigen-presenting cells (APCs) but elevated immune checkpoint T cell immunoreceptor with Ig and ITIM domains (TIGIT) expression on CD4⁺ T cells and APCs. There was no difference in the expressions of other immune checkpoints, such as programmed death-1 receptor ligand and T-cell immunoglobulin and mucin domain-containing protein 3. More CD4⁺ T cells near epithelial cells (tumor cells) and APCs expressed TIGIT in CLCG-mutant PDACs. Additionally, CLCG-mutant PDACs displayed a malfunctional immune cell crosstalk. Single-cell RNA-sequencing data confirmed the elevated TIGIT expression on CD4⁺ T cells and increased exhausted CD4⁺ T cells in CLCG-low PDACs. These findings uncovered the unique underlying mechanisms of immune suppression in CLCG-deficient PDACs and identified CLCG as potential biomarkers to identify those who may benefit from TIGIT-targeting immunotherapies.

Keywords: CD4(+) T cells; epigenetic regulation; immunosuppression; pancreatic ductal adenocarcinoma; tumor microenvironment.