HHLA2, a member of the B7 family, is expressed in human osteosarcoma and is associated with metastases and worse survival

Abstract

Over the past four decades there have been minimal improvements in outcomes for patients with osteosarcoma. New targets and novel therapies are needed to improve outcomes for these patients. We sought to evaluate the prevalence and clinical significance of the newest immune checkpoint, HHLA2, in osteosarcoma. HHLA2 protein expression was evaluated in primary tumor specimens and metastatic disease using an osteosarcoma tumor microarray (TMA) (n = 62). The association of HHLA2 with the presence of tumor infiltrating lymphocytes (TILs) and five-year-event-free-survival were examined. HHLA2 was expressed in 68% of osteosarcoma tumors. HHLA2 was expressed in almost all metastatic disease specimens and was more prevalent than in primary specimens without known metastases (93% vs 53%, p = 0.02). TILs were present in 75% of all osteosarcoma specimens. Patients whose tumors were ≥25% or ≥50% HHLA2 positive had significantly worse five-year event-free-survival (33% vs 64%, p = 0.03 and 14% vs 59%, p = 0.02). Overall, we have shown that HHLA2 is expressed in the majority of osteosarcoma tumors and its expression is associated with metastatic disease and poorer survival. Along with previously reported findings that HHLA2 is a T cell co-inhibitor, these results suggest that HHLA2 may be a novel immunosuppressive mechanism within the osteosarcoma tumor microenvironment.

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].…”

The expanding repertoire of targets for immune checkpoint inhibition in bladder cancer: What lies beneath the tip of the iceberg, PD-L1

“…Similarly, EGFR mutational status and high tumor-infiltrating lymphocyte density are associated with HHLA2 expression in non–small cell lung carcinoma [82]. In osteosarcoma, HHLA2 expression is associated with advanced disease and almost universally found in metastatic specimens, and confers a poorer prognosis [83]. HHLA2 is also overexpressed in over half of high-grade urothelial tumors [84].…”

CD28 family of receptors inter-connect in the regulation of T-cells

“…B7H7 is believed to interact with CD28H via its first IgV domain and to send a co-stimulatory signal [37] , or co-inhibitory signal in the presence or absence of CD28H expression [38,41] . Aberrant expression of B7H7 has been observed in various cancer types including lung [42] osteosarcoma [43] and pancreatic cancers [44] . Other recently identified B7 family members whose overexpression correlate with poor cancer prognosis include B7H4 (B7x, B7S1, VTCN1) and B7H5 (PD-1H, VISTA, GI24, DIES1).…”