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

Abstract

Background: 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.Methods: 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.Results: 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.Conclusion: 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.

Comprehensive Analysis of M6A-Related lncRNAs, Immune Checkpoints and Immune Infiltrates in Clear Cell Renal Cell Carcinoma

“…CTLA4, CD274, PDCD1, PDCD1LG2, HAVCR2, TIGIT, and LAG3 were reported to be elevated and might trigger cell apoptosis in ccRCC by Liao et al [16]. In ccRCC patients, CTLA4 expression was positively linked to 22 immune cells, and patients with high CTLA4 expression had shorter survival times, as previously shown [14,13,30]. Targeting immune checkpoints has been one of the most successful treatments for malignant tumors in recent years [15,[31][32][33][34].…”

“…Immune checkpoints secreted by immune cells can inhibit the function of immune cells. Some immune checkpoints, including as CTLA4, TIGIT, CD19, PDCD1, and LAG3, have been found in ccRCC [14][15][16][17], although their correlations with m 6 A-related lncRNAs have yet to be determined [18,19].…”

ISPRF: a machine learning model to predict the immune subtype of kidney cancer samples by four genes

“…A previous study found that CTLA4 expression value was strongly correlated with the levels of T cells in 33 cancer types (39). But CTLA4 usually negatively regulates T cell activation and was accompanied by an immunosuppressed phenotype (40). FOXP3 could reprogram T cell metabolism, improve the T-regulatory cells (Tregs), and suppress the cell function and proliferation of CD8+ T cells (41).…”

Integrated Bioinformatic Analysis of DNA Methylation and Immune Infiltration in Endometrial Cancer

“…CIBERSORT is broadly performed to explore the abundance of immune cells in normal and tumor tissues [16,17]. Many recent studies have examined the role of immune cells in TME in the mechanism of cancers, such as prostate cancer [18], clear cell renal cell carcinoma [19], and endometrial cancer [20]. However, few have studied the disease mechanism and prognosis biomarkers related to DNA methylation and immune cell infiltration.…”