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.
Highlights
Immunotherapy has shown remarkable therapeutic effects in anti-tumor therapy
To contribute to the understanding of these discrepancies, we investigated the expression profiling and prognostic value of Human endogenous retro virus-H Long repeat-associating 2 (HHLA2) in human cancer according to multiple public databases and investigated what transcription factor may be associated with the dysregulation of HHLA2 in Kidney Clear Cell Carcinoma (KIRC), our finding may be helpful for the further study on HHLA2
Previous studies have reported that it was widely expressed in patients with PD-1-negative non-small-cell lung cancer (NSCLC), which suggests HHLA2 might be promising immunotherapy target for tumor patients who do not response to PD-1 related therapy [15]
Summary
Immunotherapy has shown remarkable therapeutic effects in anti-tumor therapy. Prognostic Significance of HHLA2 in Human Tumors on the surface of the cell membrane of antigen presenting cell (APC) binds to the CD28 molecule on the surface of T lymphocyte, providing an initial costimulatory signal for the activation of T lymphocyte. After this costimulatory signal, coinhibitory molecule (such as CTLA-4 and PD-1) of CD28 family on the surface of T lymphocyte binds to B7-1/B72 to inhibit T lymphocyte activation [2, 3], this interaction mediated T lymphocyte co-stimulation and co-suppression lay the foundation of the regulation of anti-tumor immune responses [4, 5]. Since PD-1 is only expressed in part of NSCLC, finding new broader expressed immune checkpoint will be important for improving the response rate of immunotherapy [15]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
