Overexpression of HHLA2, a member of the B7 family, is associated with worse survival in human colorectal carcinoma

Abstract

BackgroundColorectal carcinoma (CRC) is one of the most common malignancies, and immunotherapy has opened a new field of cancer treatment in recent years. Generally, CRC does not benefit from immunotherapy. HHLA2, a member of the B7 family, is a novel immune checkpoint molecule, and the prognostic value of HHLA2 in CRC patients and the association between HHLA2 expression and clinicopathological characteristics remains unknown.Materials and methodsThis study included 63 patients diagnosed with CRC, and their resected specimens were obtained and constructed as a tissue microarray. Expression of HHLA2 and CD8 was detected by the double immunohistochemistry method. Based on follow-up data, correlations of HHLA2 expression and clinicopathological features, including overall survival, in CRC patients were evaluated.ResultsHigh HHLA2 expression was detected in CRC tumor tissues, compared to the adjacent noncancerous tissues. HHLA2 expression level was significantly related to the depth of invasion (P=0.044) and CD8+ T-cell infiltration status (P=0.016), and predicted high mortality rate (P=0.035). HHLA2 acted as an independent predictive factor in the overall survival of CRC patients (P=0.039, hazard ratio=2.162, 95% CI 1.041–3.084).ConclusionHHLA2 expression is upregulated in CRC patients, and HHLA2 is an independent prognostic factor of overall survival of CRC patients. High HHLA2 expression is closely correlated with CD8 T-cell infiltration status and can predict poor prognosis in CRC patients.

Immune Checkpoint Human Endogenous Retrovirus-H Long Terminal Repeat-Associating Protein 2 is Upregulated and Independently Predicts Unfavorable Prognosis in Bladder Urothelial Carcinoma

“…Previous studies have shown that HHLA2 is negatively expressed in most human tissues, whereas it is overexpressed in a variety of cancers [12]. High HHAL2 expression is associated with poor survival in patients with breast cancer, colon cancer, clear cell renal cell carcinoma, gastric cancer, or osteosarcoma [12,13,[16][17][18]. Consistently, in this study, we found that HHLA2 is upregulated in BUC tissues compared with normal tissues, and high HHLA2 expression predicts poor survival in BUC patients.…”

“…Numerous studies have demonstrated that pathological grading and clinical tumor staging play pivotal roles are associated with lymph node metastasis and predict clinical prognosis of patients with BCa in clinical practice. It has been reported previously that high HHLA2 expression is correlated with metastasis in lung cancer, colorectal cancer, and osteosarcoma [13,18,19]. In this study, we found that a high expression of HHLA2 is also significantly associated with lymph node metastasis and HHLA2 is an independent factor of lymph node metastasis in BUC.…”

“…The widespread expression of HHLA2 indicates that HHLA2 probably plays a pivotal role in tumor development and progression [12]. Consistently, other studies showed that HHLA2 acts as a prognostic biomarker in several cancers, such as colorectal carcinoma, clear cell renal cell carcinoma, gastric cancer, and osteosarcoma [13,[16][17][18]. In non-small-cell lung carcinoma, HHLA2 expression is reported to be associated with EGFR mutation and high tumor-infiltrating lymphocyte density [19].…”

“…HHLA2 was found to be a gene in the immunoglobulin (Ig) superfamily during the screening of human genome for the LTR sequences (which provide polyadenylation signals) of HERV [13]. HHLA2 is a membrane protein with 3 Ig-like domains (IgV-IgC-IgV), whereas other members of the B7 family typically have only 2 Ig domains (IgV-IgC) [14].…”

A Six-LncRNA Expression Signature Associated with Prognosis of Colorectal Cancer Patients

“…Despite the significant advances of custom treatment method, the high migration and invasion capacity have been a bottle-neck for eliminating the mortality, which kept the 5-year survival rate of CRC under 12% [2][3][4]. In addition, several other factors were also identified to influence CRC prognosis, such as health-related quality of life [5], genome stability [6,7], aberrant gene expression [8,9], etc. However, the mechanism underlying CRC survival remains elusive, which impedes the improvement of CRC prognosis.…”