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Prognostic Significance of Potential Immune Checkpoint Member HHLA2 in Human Tumors: A Comprehensive Analysis.

ABSTRACT: Immunological checkpoint inhibitors have been immensely successfully applied in the treatment of cancer, however, a portion of tumor patients can't benefit from checkpoint therapy. The low PD-1/CTLA-4 positive rate and involvement of multiple immunosuppressive pathways are thought to be one of the reasons for treatment failure in non-responding patients. A new immune checkpoint molecule, HHLA2, which was widely expressed in PD-1 negative human tumors, may be a promising target for the improvement of recent immune therapy. Yet, the prognostic value and transcriptional regulatory mechanisms of HHLA2 remains unclear. In this study, we aimed to evaluate the prognostic value and transcriptional regulation mechanism of HHLA2 according to clinical and experimental data from multiple databases, including cBioPortal, TCGA, Cistrome, TIMER, Oncomine, Kaplan-Meier, GeneXplain. It was found that the expression of HHLA2 was significantly elevated in renal tumors, and significantly decreased in colorectal tumors. Pan-cancer survival analysis indicates that HHLA2 was an independent prognostic factor in 9/20 of human cancers. Especially in renal clear cell carcinoma (P = 3.0E-7). Through plotting survival curve in Kaplan-Meier Plotter, it was found that hypomethylation of HHLA2 DNA was a favorable prognostic factor for KIRC patients. Yet, the copy number variant of HHLA2 was not significantly correlated with the overall survival of KIRC patients. Finally, by analyzing the motif of HHLA2 co-expression genes, we identified 15 transcription factors that may be involved in the regulation of the HHLA2 co-expression network. Among these transcription factors, BATF in B lymphocyte and SMAD in monocyte were confirmed to be able to directly bind to HHLA2 DNA according to chip-seq experimental data from Cistrome database.

SUBMITTER: Wang B

PROVIDER: S-EPMC6644528 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Prognostic Significance of Potential Immune Checkpoint Member HHLA2 in Human Tumors: A Comprehensive Analysis.

Wang Ben B Ran Zhujie Z Liu Mengmeng M Ou Yunsheng Y

Frontiers in immunology 20190715

Immunological checkpoint inhibitors have been immensely successfully applied in the treatment of cancer, however, a portion of tumor patients can't benefit from checkpoint therapy. The low PD-1/CTLA-4 positive rate and involvement of multiple immunosuppressive pathways are thought to be one of the reasons for treatment failure in non-responding patients. A new immune checkpoint molecule, HHLA2, which was widely expressed in PD-1 negative human tumors, may be a promising target for the improvemen ...[more]

PMID: 31379814

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Project description:PurposeHHLA2 (B7H7/B7-H5/B7y) is a newly identified B7 family member that regulates human T-cell functions. However, its protein expression in human organs and significance in human diseases are unknown. The objective of this study was to analyze HHLA2 protein expression in normal human tissues and cancers, as well as its prognostic significance, to explore mechanisms regulating HHLA2 expression, and to identify candidate HHLA2 receptors.Experimental designAn immunohistochemistry protocol and a flow cytometry assay with newly generated monoclonal antibodies were developed to examine HHLA2 protein. HHLA2 gene copy-number variation was analyzed from cancer genomic data. The combination of bioinformatics analysis and immunologic approaches was established to explore HHLA2 receptors.ResultsHHLA2 protein was detected in trophoblastic cells of the placenta and the epithelium of gut, kidney, gallbladder, and breast, but not in most other organs. In contrast, HHLA2 protein was widely expressed in human cancers from the breast, lung, thyroid, melanoma, pancreas, ovary, liver, bladder, colon, prostate, kidney, and esophagus. In a cohort of 50 patients with stage I-III triple-negative breast cancer, 56% of patients had aberrant expression of HHLA2 on their tumors, and high HHLA2 expression was significantly associated with regional lymph node metastasis and stage. The Cancer Genome Atlas revealed that HHLA2 copy-number gains were present in 29% of basal breast cancers, providing a potential mechanism for increased HHLA2 protein expression in breast cancer. Finally, Transmembrane and Immunoglobulin Domain Containing 2 (TMIGD2) was identified as one of the receptors for HHLA2.ConclusionsWide expression of HHLA2 in human malignancies, together with its association with poor prognostic factors and its T-cell coinhibitory capability, suggests that the HHLA2 pathway represents a novel immunosuppressive mechanism within the tumor microenvironment and an attractive target for human cancer therapy.

Project description:Glioma is the most common and aggressive tumor type of the central nervous system and is associated with poor prognosis. To date, novel emerging immunotherapies have significantly improved outcomes for patients with various cancer types. Human endogenous retrovirus‑H long terminal repeat‑associating protein 2 (HHLA2), a newly discovered immune checkpoint molecule, has demonstrated its potential as a novel therapeutic target. Therefore, the present study aimed to investigate the clinical prognostic value of HHLA2 in gliomas and its mechanistic role. A systematic review of datasets from The Cancer Genome Atlas was performed. The RNA‑seq data of a total of 669 cases were analyzed and the biological function of HHLA2 was predicted by Gene Ontology (GO) and pathway enrichment analysis. Immunohistochemistry labelling images for HHLA2 was obtained from the Human Protein Atlas. xCell was used to comprehensively analyze the model of tumor‑infiltrating immune cell in glioma. The Cox proportional hazards regression model was used to predict outcomes for glioma patients. The results revealed that the expression levels of HHLA2 were significantly lower in high‑grade glioma, as well as glioma with wild‑type isocitrate dehydrogenase, no deletion of 1p/19q and telomerase reverse transcriptase promoter mutation. Receiver operating characteristic analysis revealed that HHLA2 was a predictor of the neural subtype. The tumor‑infiltrating immune cell model indicated that HHLA2 was negatively associated with tumor‑associated macrophages. GO analysis and pathway enrichment analysis revealed that HHLA2‑associated genes were functionally involved in inhibition of neoplasia‑associated processes. HHLA2 was significantly negatively correlated with certain genes, including interleukin‑10, transforming growth factor‑β, vascular endothelial growth factor and δ‑like canonical Notch ligand 4, and other immune checkpoint molecules, including programmed cell death 1, lymphocyte activating 3 and CD276. Survival analysis indicated that high expression of HHLA2 predicted a favorable prognosis. In conclusion, the present study revealed that upregulation of HHLA2 is significantly associated with a favorable outcome for patients with glioma. Targeting HHLA2 as an immune stimulator may become a valuable approach for the treatment of glioma in clinical practice.

Dataset Information

Prognostic Significance of Potential Immune Checkpoint Member HHLA2 in Human Tumors: A Comprehensive Analysis.

Publications

Prognostic Significance of Potential Immune Checkpoint Member HHLA2 in Human Tumors: A Comprehensive Analysis.

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