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

Abstract

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 T_RM-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.