CD82-associated exhausted CD8+ T cells define prognosis and immunotherapy resistance in colon cancer

TL;DR

CD82 is linked to exhausted T cells in colon cancer, affecting prognosis and resistance to immunotherapy.

Contribution

CD82 is identified as a novel marker and driver of CD8+ T cell exhaustion in colon cancer.

Findings

CD82 is highly expressed in exhausted CD8+ T cells and correlates with poor survival in colon cancer.

CD82+TIM-3+PD-1+ CD8+ T cells are associated with immunotherapy resistance and worse clinical outcomes.

BATF and BHLHE40 are potential regulators of CD82 in T cell exhaustion.

Abstract

The regulation of T cell exhaustion within the tumor microenvironment plays a pivotal role in shaping the immune response to cancer and determining the efficacy of immunotherapy. However, the molecular factors governing this process in colon cancer remain poorly understood. This study investigates the expression characteristics and functional significance of the transmembrane protein CD82 in the colon cancer immune microenvironment, with emphasis on its regulatory role in CD8+ T cell exhaustion and clinical outcomes. Publicly available transcriptomic datasets were integrated with multiplex immunohistochemistry on colon cancer tissue microarrays to characterize the cell–type–specific distribution of CD82 and its associations with key markers of T cell dysfunction. CD82 expression was markedly increased in tumor-infiltrating immune and epithelial cells compared with normal tissues, particularly within exhausted CD8+ T cells. Elevated CD82 levels showed strong positive correlations with canonical exhaustion markers such as programmed cell death protein 1 and T cell immunoglobulin and mucin domain-containing protein 3. Multiplex immunohistochemical analysis further revealed that enrichment of CD82-positive epithelial regions and expansion of the CD82+TIM-3+PD-1+CD8+ T cell subset were associated with poor prognosis and were confirmed by multivariate Cox regression as independent risk factors for unfavorable survival. In patients who failed to achieve a complete pathological response following immunotherapy, exhausted CD8+ T cells exhibited significantly higher CD82 expression. Single-cell regulatory network analysis identified BATF and BHLHE40 as potential transcriptional regulators of CD82. Collectively, these findings demonstrate that CD82 promotes CD8+ T cell exhaustion, contributing to tumor progression and immunotherapy resistance in colon cancer. This study provides novel insight into the molecular mechanisms underlying immune dysfunction and offers a potential therapeutic target for reversing immunosuppression and improving immunotherapy efficacy in colon malignancies.

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