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.

抗肿瘤 T 细胞免疫反应的负调控有助于肿瘤免疫逃逸。^{在这里，我们展示了 T 细胞中 CD147（一种 I 型跨膜分子）的缺失以 CD8 +} T 细胞依赖性方式强烈限制了小鼠黑色素瘤和肺癌的体内肿瘤生长。在小鼠肿瘤模型中，CD8 ⁺肿瘤浸润淋巴细胞 (TIL) 上的 CD147 表达上调，并且 CD147 与两种免疫检查点分子 Tim-3 和 PD-1 共表达。^{挖掘转移性黑色素瘤患者肿瘤活检中 CD8 +} TILs 的公开可用基因分析数据显示，耗尽的 CD8 ⁺ TILs中 CD147 表达水平高于其他 CD8 ^{+ TIL 子集}TIL，以及 PD-1 和 TIM-3 的表达。此外，CD147 缺失增加了 TIL 的丰度、CD8 ⁺ T 细胞的细胞毒性效应功能和 PD-1 ⁺ CD8 ⁺ TIL 的频率，并部分逆转了 PD-1 ⁺ Tim-3 ⁺ CD8 ⁺ TIL 的功能失调状态。细胞毒性转录因子 Runx3 和 T-bet 介导增强了 CD147 ^–/– CD8 ⁺ T 细胞的抗肿瘤反应。此外，T 细胞中的 CD147 缺失增加了 T _RM的频率样细胞和 T 细胞趋化因子 CXCL9 和 CXCL10 在肿瘤微环境中的表达。对来自非小细胞肺癌患者的肿瘤组织样本的分析显示，CD8 + TILs 上 CD147 的表达与 CD8 ^{+ TILs}的丰度、肿瘤组织样本的组织学分级和晚期肿瘤患者的生存率呈负相关。^{总之，我们发现了 CD147 作为由 CD8 +} TIL介导的抗肿瘤反应的负调节剂的新功能，并将 CD147 确定为癌症免疫治疗的潜在靶点。