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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.

SUBMITTER: Chen Y

PROVIDER: S-EPMC8322173 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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

Chen Yatong Y Xu Jing J Wu Xiaodong X Yao Hui H Yan Zhou Z Guo Ting T Wang Wenjing W Wang Peixiao P Li Yu Y Yang Xiangmin X Li Hao H Bian Huijie H Chen Zhi-Nan ZN

Cellular & molecular immunology 20201111 8

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 ...[more]

PMID: 33177695

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Project description:BackgroundAn in-depth understanding of immune evasion mechanisms in tumors is crucial to overcome resistance and enable innovative advances in immunotherapy. Circular RNAs (circRNAs) have been implicated in cancer progression. However, much remains unknown regarding whether circRNAs impact immune escape in non-small-cell lung carcinoma (NSCLC).MethodsWe performed bioinformatics analysis to profile and identify the circRNAs mediating immune evasion in NSCLC. A luciferase reporter assay, RNA immunoprecipitation (RIP), RNA pulldown assays and fluorescence in situ hybridization were performed to identify the interactions among circIGF2BP3, miR-328-3p, miR-3173-5p and plakophilin 3 (PKP3). In vitro T cell-mediated killing assays and in vivo syngeneic mouse models were used to investigate the functional roles of circIGF2BP3 and its downstream target PKP3 in antitumor immunity in NSCLC. The molecular mechanism of PKP3-induced PD-L1 upregulation was explored by immunoprecipitation, RIP, and ubiquitination assays.ResultsWe demonstrated that circIGF2BP3 (hsa_circ_0079587) expression was increased in NSCLC and negatively correlated with CD8+ T cell infiltration. Functionally, elevated circIGF2BP3 inactivated cocultured T cells in vitro and compromised antitumor immunity in an immunocompetent mouse model, and this effect was dependent on CD8+ T cells. Mechanistically, METTL3 mediates the N6-methyladenosine (m6A) modification of circIGF2BP3 and promotes its circularization in a manner dependent on the m6A reader protein YTHDC1. circIGF2BP3 competitively upregulates PKP3 expression by sponging miR-328-3p and miR-3173-5p to compromise the cancer immune response. Furthermore, PKP3 engages with the RNA-binding protein FXR1 to stabilize OTUB1 mRNA, and OTUB1 elevates PD-L1 abundance by facilitating its deubiquitination. Tumor PD-L1 deletion completely blocked the impact of the circIGF2BP3/PKP3 axis on the CD8+ T cell response. The inhibition of circIGF2BP3/PKP3 enhanced the treatment efficacy of anti-PD-1 therapy in a Lewis lung carcinoma mouse model. Collectively, the PKP3/PD-L1 signature and the infiltrating CD8+ T cell status stratified NSCLC patients into different risk groups.ConclusionOur results reveal the function of circIGF2BP3 in causing immune escape from CD8+ T cell-mediated killing through a decrease in PD-L1 ubiquitination and subsequent proteasomal degradation by stabilizing OTUB1 mRNA in a PKP3-dependent manner. This work sheds light on a novel mechanism of PD-L1 regulation in NSCLC and provides a rationale to enhance the efficacy of anti-PD-1 treatment in NSCLC.

Dataset Information

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

Publications

CD147 regulates antitumor CD8<sup>+</sup> T-cell responses to facilitate tumor-immune escape.

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