CTLA4 has a profound impact on the landscape of tumor-infiltrating lymphocytes with a high prognosis value in clear cell renal cell carcinoma (ccRCC)

Cancer Cell International

Yaqi Fan¹  Yeqiang Liu²  Shiyi Liu³  Zhimin Deng³  Dongyong Yang³  Wei Tan³  Mengqin Yuan³  Yanxiang Cheng³  Yajing Zheng³  Fangfang Dai³  Yanqing Wang³  Li Zhang³  Feiyan Wang⁴ 

[1] Department of Dermatopathology, Shanghai Skin Disease Hospital, Tongji University School of Medicine, 200071, Shanghai, Shanghai, People’s Republic of China;Department of Dermatopathology, Shanghai Skin Disease Hospital, Tongji University School of Medicine, 200071, Shanghai, Shanghai, People’s Republic of China;Department of Dermatopathology, Shanghai Skin Disease Clinical College of Anhui Medical University, Shanghai Skin Disease Hospital, 200071, Shanghai, Shanghai, People’s Republic of China;Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, 430060, Wuhan, Hubei Province, People’s Republic of China;Shanghai Skin Disease Clinical College of Anhui Medical University, Shanghai Skin Disease Hospital, 200443, Shanghai, People’s Republic of China;

关键词: CTLA4;    Clear cell renal cell carcinoma;    Tumor microenvironment;    Tumor-infiltrating lymphocytes;    Prognosis;    CD8+ T cells;    Immune checkpoints;   

DOI  :  10.1186/s12935-020-01603-2

来源: Springer

【 摘 要 】

BackgroundCytotoxic T-lymphocyte associated protein 4 (CTLA4) inhibitors have been shown to significantly prolong the overall survival (OS) in a wide range of cancers. However, its application in clear cell renal cell carcinoma (ccRCC) is limited due to the therapy response, and the prognostic value of CTLA4 in ccRCC has not been investigated in detail.MethodsBy using immunohistochemistry, Kaplan–Meier (K–M) analysis, uni- and multi-variate Cox analysis, we comprehensively and systematically studied the prognostic value of CTLA4 in ccRCC. Then, we applied Gene Ontology (GO), the Kyoto Encyclopedia of Genes and Genomes (KEGG) and CIBERSORT, ESTIMATE algorithm, ssGSEA and somatic mutation analyses to reveal the impact of CTLA4 on the landscape of tumor-infiltrating lymphocytes (TILs) infiltration and genetic mutation. Besides, given current concerns caused by combined immunotherapy, we also investigated the relationship between CTLA4 and other immune checkpoints.ResultsIn vitro experiment and data mining showed that, CTLA4 was up-regulated in ccRCC tissues and closely related to the disease progression as well as a poor prognosis. Deeper researches demonstrated that CTLA4 regulates T cell activation and was significantly linked to TIL-abundant tumor microenvironment (TME), but was accompanied by an immunosuppressed phenotype. Mutation analysis showed that CTLA4 was associated with more frequent BRCA-associated protein 1 (BAP1) mutation. Moreover, we found that CTLA4 was markedly correlated with multiple immune checkpoints, which suggested that ccRCC patients with high expressed CTLA4 may benefit more from immune checkpoint blockades (ICBs) combined therapy.ConclusionCTLA4 has a profound impact on the landscape of TILs and genetic mutation, and can be used as the biomarker with high prognosis value in ccRCC.

【 授权许可】

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