CD147 regulates antitumor CD8^(+)T-cell responses to facilitate tumor-immune escape

摘要

Negative regulation of antitumor T-cell-immune responses facilitates tumor-immune escape.Here,we show that deletion of CD147,a type I transmembrane molecule,in T cells,strongly limits in vivo tumor growth of mouse melanoma and lung cancer in a CD8^(+)T-cell-dependent manner.In mouse tumor models,CD147 expression was upregulated on CD8^(+)tumor-infiltrating lymphocytes(TILs),and CD147 was coexpressed with two immune-checkpoint molecules,Tim-3 and PD-1.Mining publicly available gene-profiling data for CD8^(+)TILs in tumor biopsies from metastatic melanoma patients showed a higher level of CD147 expression in exhausted CD8^(+)TILs than in other subsets of CD8^(+)TILs,along with expression of PD-1 and TIM-3.Additionally,CD147 deletion increased the abundance of TILs,cytotoxic effector function of CD8^(+)T cells,and frequency of PD-1^(+)CD8^(+)TILs,and partly reversed the dysfunctional status of PD-1^(+)Tim-3^(+)CD8^(+)TILs.The cytotoxic transcription factors Runx3 and T-bet mediation enhanced antitumor responses by CD147^(-/-)CD8^(+)T cells.Moreover,CD147 deletion in T cells increased the frequency of TRM-like cells and the expression of the T-cell chemokines CXCL9 and CXCL10 in the tumor microenvironment.Analysis of tumor tissue samples from patients with non-small-cell lung cancer showed negative correlations between CD147 expression on CD8^(+)TILs and the abundance of CD8^(+)TILs,histological grade of the tumor tissue samples,and survival of patients with advanced tumors.Altogether,we found a novel function of CD147 as a negative regulator of antitumor responses mediated by CD8^(+)TILs and identified CD147 as a potential target for cancer immunotherapy.