Cholesterol increases expression of exhaustion markers in tumor-infiltrating CD8+ T cells.
Major Finding: Cholesterol increases expression of exhaustion markers in tumor-infiltrating CD8+ T cells.
Clinical Relevance: Cholesterol reduction or XBP1 inhibition may enhance the efficacy of immune checkpoint inhibitors.
Impact: Tumor microenvironment–induced T-cell exhaustion can be overcome by modulating cholesterol levels.
Tumor microenvironments can be immunosuppressive and promote T-cell exhaustion. Although immunotherapeutic strategies that alleviate this exhaustion effect can be efficacious, intrinsic resistance limits the utility of these approaches. Ma and colleagues found that high intracellular cholesterol levels positively correlated with exhaustion marker levels in CD8+ T cells in metastatic lung lesions in a mouse melanoma model and that intracellular cholesterol levels increase in T cells after tumor homing. These initial observations were confirmed in human patient samples, as cholesterol content in CD8+ T cells isolated from primary colon tumors or myeloma samples correlated with increased PD-1 and 2B4 expression. Cholesterol also increased transcription levels of Pdcd1 (which encodes PD-1) and induced other markers of exhaustion in a dose-dependent manner in vitro. Gene expression analysis revealed that cholesterol exposure significantly increased the expression of ER stress-response genes, including XBP1. Treatment with an ER stress inhibitor or XBP1 knockdown blocked the exhaustion effects of cholesterol exposure and inhibited cholesterol-induced increased PD-1 and 2B4 expression. ChIP profiling and transcriptional reporter assays revealed that cholesterol increases PD-1 expression in part by increasing XBP1 occupancy at the Pdcd1 promoter. XBP1 knockdown or treatment with an ER stress inhibitor decreased PD-1 and 2B4 expression on tumor-infiltrating CD8+ T cells and also significantly decreased tumor burden, suggesting that cholesterol-induced ER stress affected T-cell antitumor functionality. Together, these data highlight the importance of the tumor microenvironment in regulating immune checkpoints such as PD-1 and suggest that cholesterol reduction or ER stress response inhibition might enhance the antitumor efficacy of anti–PD-1 immunotherapies.
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