CTLA4 has a profound impact on the landscape of tumor-infiltrating lymphocytes with a high prognosis value in clear cell renal cell carcinoma (ccRCC).
CTLA4 has a profound impact on the landscape of tumor-infiltrating lymphocytes with a high prognosis value in clear cell renal cell carcinoma (ccRCC).
复制标题
CTLA4对透明细胞肾细胞癌（CCRCC）的预后价值高的肿瘤淋巴细胞的景观具有深远的影响。
DOI：
10.1186/s12935-020-01603-2
复制
发表时间：
2020
影响因子：
5.8
通讯作者：
Cheng Y
中科院分区：
文献类型：
--
作者：
Liu S;Wang F;Tan W;Zhang L;Dai F;Wang Y;Fan Y;Yuan M;Yang D;Zheng Y;Deng Z;Liu Y;Cheng Y
细胞毒性T淋巴细胞相关蛋白4（CTLA 4）抑制剂已被证明可显著延长多种癌症的总生存期（OS）。然而，由于治疗反应，其在透明细胞肾细胞癌（ccRCC）中的应用受到限制，并且尚未详细研究CTLA 4在ccRCC中的预后价值。本研究采用免疫组化、Kaplan-Meier（K-M）分析、单因素和多因素考克斯分析等方法，全面系统地研究了CTLA 4在ccRCC中的预后价值。然后，我们应用基因本体论（GO），基因和基因组的京都百科全书（KEGG）和CIBERSORT，ESTIMATE算法，ssGSEA和体细胞突变分析，以揭示CTLA 4的肿瘤浸润淋巴细胞（TIL）的浸润和基因突变的景观的影响。此外，鉴于目前联合免疫治疗引起的担忧，我们还研究了CTLA 4与其他免疫检查点之间的关系。体外实验和数据挖掘显示，CTLA 4在ccRCC组织中表达上调，与疾病进展及预后不良密切相关。更深入的研究表明，CTLA 4调节T细胞活化，并与TIL丰富的肿瘤微环境（TME）显着相关，但伴随着免疫抑制表型。突变分析显示CTLA 4与更频繁的BRCA相关蛋白1（BAP 1）突变相关。此外，我们发现CTLA 4与多个免疫检查点显著相关，这表明CTLA 4高表达的ccRCC患者可能从免疫检查点阻断（ICBs）联合治疗中获益更多。CTLA 4对肿瘤浸润细胞的分布和基因突变有重要影响，可作为肾细胞癌预后评估的生物标志物。
Cytotoxic 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. By 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. In 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. CTLA4 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.