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. 2019 Jul 15:10:1573.
doi: 10.3389/fimmu.2019.01573. eCollection 2019.

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

Ben Wang  1 , Zhujie Ran  2 , Mengmeng Liu  3 , Yunsheng Ou  1
Affiliations

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

Ben Wang et al. Front Immunol. .

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.

Keywords: B7; HHLA2; PD-1; expression profiling; immune checkpoint.

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Figures

Figure 1
Figure 1
The figure shows the distribution of HHLA2 in various human tissues.
Figure 2
Figure 2
Pan-cancer expression profiling analysis of HHLA2. (A) Interactive body map of HHLA2 mRNA expression constructed by GEPIA (TCGA), the darker color corresponds to the higher gene expression level. Red means the median expression of HHLA2 from tumor samples, and the green is from normal samples. (B) The length of the bar corresponds to the number of studies show significant over or under expression of HHLA2 vs. normal tissue (the number of significantly differently expressed GEO clinical cohorts). (C) The boxplot shows the pan-cancer expression profiling of HHLA2 in human cancers. The below row refers to the standard abbreviations of tumor in TCGA. The color refers to the tumor (red) or normal (blue). P-value Significant Codes: 0 ≤ *** < 0.001 ≤ ** < 0.01 ≤ * < 0.05 ≤. < 0.1.
Figure 3
Figure 3
Forest plot shows the result of pan-cancer survival analysis. The upper subgroups are composed of studies whose P-value is <0.05, the below subgroups are more than 0.05.
Figure 4
Figure 4
The boxplot shows the correlation between the expression of HHLA2 and the pathological grade in KIRC (left:from GSE22541, right: GSE40435). The label at the top of the picture corresponds to the pathological stage of the patient.
Figure 5
Figure 5
The Heatmap and Kaplan Meier curves of expression level, methylation status, copy number variant of HHLA2. (A) The heatmap shows the expression level, methylation status, copy number variant of HHLA2 in the TCGA database, determined by UCSC Xena. (B–D) Kaplan Meier plot shows the over-expression and hypomethylation of HHLA2 is favorable prognostic factor for KIRC patients.
Figure 6
Figure 6
Venn plot and Metascape enrichment result of co-expression genes of HHLA2. (A) The intersection of Venn plot is considered to be co-expressed genes of HHLA2. (B) The bar plot of HHLA2 co-expression gene enrichment term.
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