CTLA-4 correlates with immune and clinical characteristics of glioma

Wang

Tan

et al. 2020

Preprint

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.

Section: Discussionmentioning

confidence: 99%

Section: Ctla4 Was Highly Related To Other Immune Checkpoint Moleculesmentioning

confidence: 99%

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

Wang

Tan

et al. 2020

Preprint

“…Differential expression of 7 established immune checkpoint genes in the low and high-risk groups was analyzed. These are, T cell immunoglobulin domain and mucin domain 3 (TIM3), programmed cell death 1 (PD1), PD1 interacts with programmed death ligand 1 (PDL1), cytotoxic T lymphocyte antigen 4 (CTLA4), T cell immunoreceptor with Ig and ITIM domains (TIGIT), long non-coding RNA MIR 155 host gene (MIR155HG), and CD48 [20][21][22][23][24] . This analysis evaluated the correlation between risk score and expression of the checkpoint genes.…”

Section: Analysis Of Correlation Between Risk Score and Expression Ofmentioning

confidence: 99%

A 1p/19q Codeletion-Associated Immune Signature for Predicting Lower Grade Glioma Prognosis

et al. 2020

Cell Mol Neurobiol

Background: Lower grade gliomas (LGGs) with codeletion of chromosomal arms 1p and 19q (1p/19 codeletion) has a favorable outcome. However, its overall survival (OS) varies. Here, we established an immune signature associated with 1p/19q codeletion for accurate prediction of prognosis of LGGs. Methods: We extracted RNA sequencing and corresponding clinical data of LGGs from the Chinese Glioma Genome Atlas (CGGA) and The Cancer Genome Atlas (TCGA). The CGGA and TCGA databases were dichotomized into training group and testing group. The immune-related differentially expressed genes (DEGs) associated with 1p/19q codeletion were screened using Cox proportional hazards regression analyses. A prognostic signature was established using dataset from CGGA and tested in TCGA datasets. Subsequently, we explored the correlation between the prognostic signature and immune response. Results: Thirteen immune genes associated with 1p/19q codeletion were identi ed and used to construct a prognostic signature. The 1-, 3-, 5-year survival rates of the low-risk group were approximately 97%, 89%, and 79%, while those of the high-risk group were 81%, 50% and 34%, respectively in the training group. The nomogram which comprised of age, world health organization (WHO) grade, primary or recurrent types, 1p/19q codeletion status and risk score provided accurate prediction for the survival rate of glioma. DEGs that were highly expressed in the high-risk group clustered with many immune-related pathways. Immune checkpoints including T cell immunoglobulin domain and mucin domain 3 (TIM3), programmed cell death 1 (PD1), PD1 interacting with programmed death ligand 1 (PDL1), cytotoxic T lymphocyte antigen 4 (CTLA4), T cell immunoreceptor with Ig and ITIM domains (TIGIT), long non-coding RNA MIR 155 host gene (MIR155HG), and CD48 were correlated with the risk score. VAV3 and TNFRFSF11B were found to be candidate immune checkpoints. Conclusion: The 1p/19q codeletion-associated immune signature provides accurate prediction of OS. VAV3 and TNFRFSF11B are novel immune checkpoints.

“…CTLA4 negatively regulated T cell activation by blocking the function of costimulatory signal and differentiation cluster CD28: B7 binding (33). CTLA4 inhibitors reverse the inhibitory immune signal and restore the anti-cancer response by blocking the interaction between CTLA4 and the ligand expressed by antigen presenting cells (30). With approval of CTLA4 inhibitor Ipilimumab for clinical applications, it has been used for metastatic melanoma after the rst-line treatment (13).…”

Section: Discussionmentioning

confidence: 99%

“…D Planchard et al reported that combination immunotherapy of PD-L1 and CTLA4 considerably prolonged the OS in advanced refractory colorectal cancer (29). Combination immunotherapy tends to replace monotherapy, for that the combinational usage of ICBs can produce higher synergistic anti-tumor e ciency and reduce side effects (30). Therefore, we continued to explore the correlation between CTLA4 and other immune checkpoint molecules, including PDCD1 (PD-1), CD274 (PD-L1), LAG3, indoleamine-2,3-dioxygenase-1 (IDO1), and TIGIT (31) (32).…”

Section: Ctla4 Was Highly Related To Other Immune Checkpoint Moleculesmentioning

confidence: 99%

CTLA4 had a profound impact in the landscape of tumor-infiltrating lymphocytes with a high prognosis value in ccRCC

Wang

Tan

et al. 2020

Preprint

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 is limited due to the therapy response and the prognostic value of CTLA4 in Clear cell renal cell carcinoma (ccRCC), which is the most common and fatal histological subtype in renal cell carcinoma, have not been investigated in detail. Methods In this study, we comprehensively and systematically studied the prognostic value of CTLA4 in ccRCC and its impact on the landscape of tumor-infiltrating lymphocytes (TILs) infiltration and genetic mutation through in vitro experiment and data mining. Results Our results showed that the CTLA4 was up-regulated in both ccRCC tissues and cell lines, and closely related to the disease progression as well as a poor prognosis. Deeper researches demonstrated that CTLA4 regulated the T cell activation and significantly linked to TIL-abundant tumor microenvironment (TME), but companies with an immunosuppressed phenotype, and CTLA4 was associated with more frequent BRCA-associated protein 1 (BAP1) mutation. Furthermore, given the current concerns caused by combined immunotherapy, we also 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 had a profound impact on the landscape of TILs and genetic mutation, as well as can be used as the biomarker with high prognosis value.