Clinical Significance of the HHLA2 Protein in Hepatocellular Carcinoma and the Tumor Microenvironment

Abstract

Background The protein “human endogenous retrovirus H long terminal repeat-associating 2” (HHLA2), a member of the B7 family, has been linked to cancer progression and immune responses. However, its functional role in hepatocellular carcinoma (HCC) remains unknown. Methods Bioinformatics was used to examine the potential roles of HHLA2 in HCC and the molecular pathways involved. Expression of HHLA2 and PD-L1 as well as the density of tumor-infiltrating lymphocytes (TILs) in tumoral areas were evaluated by immunohistochemistry and hematoxylin-eosin staining of 202 resected human HCC samples. Potential correlations of HHLA2 expression with pathological characteristics or prognosis of HCC patients were explored. Different types of immune microenvironment in HCC were defined based on HHLA2 expression and TIL density. Results High HHLA2 levels in HCC correlated with more advanced clinical cancer stage ( P = 0.040), multiple tumors ( P = 0.044), poor tumor differentiation ( P = 0.048), microvascular invasion ( P = 0.011) and hepatic capsule invasion ( P = 0.047). HHLA2 levels correlated significantly with density of TILs, but not with PD-L1 levels. High HHLA2 levels were associated with worse prognosis. Intermediate and high TIL densities were independent predictors of better prognosis. Tumor microenvironments with type I (HHLA2 - high TILs +) or type IV (HHLA2 - low TILs +) were associated with better prognosis. Conclusion HHLA2 level can independently predict worse prognosis and affect the tumor microenvironment in HCC, which may help guide immunotherapy against the cancer.

[Retracted] HHLA2 Used as a Potential Prognostic and Immunological Biomarker and Correlated with Tumor Microenvironment in Pan‐Cancer

“…In the present report, our results showed that high HHLA2 expression was correlated with poor OS in five tumors, including KICH, LAML, LIHC, and PAAD. Similarly, it was previously reported that HHLA2 expression was linked to shorter survival time in patients with clear cell renal cell carcinoma [ 7 ], gastric cancer [ 28 ], and hepatocellular carcinoma [ 29 ]. By contrast, high HHLA2 expression is predictive of a good prognosis in patients with BLCA, KIRC, READ, and SKCM.…”

HHLA2 promotes tumor progression by long non‑coding RNA H19 in human gallbladder cancer

“…However, HHLA2 can also bind to another inhibitory receptor, three immunoglobulin domains and long cytoplasmic tail 3 (KIR3DL3), which inhibits T cell action (16). In terms of cancer, higher expression levels of HHLA2 were previously reported to be associated with poorer prognoses or higher degrees of tumour invasion in lung carcinoma, hepatocellular carcinoma and prostate cancer (17)(18)(19). By contrast, in epithelial ovarian cancer, higher HHLA2 expression levels were demonstrated to be associated with superior survival outcomes and reduced tumor growth (20).…”

Tertiary Lymphatic Structures in Primary Hepatic Carcinoma: Controversy Cannot Overshadow Hope

“…In HCC, iTLSs are related to a good prognosis and can reduce the risk of early recurrence of HCC. Moreover, the upregulation of iTLS-related genes can also reduce the risk of HCC recurrence in the early and middle stages, which indicates that iTLS may be related to the existence of sustained and effective anti-tumor immunity (49,(61)(62)(63)(64). In addition, the risk of HCC recurrence is also related to TLS maturity (primary or secondary follicles and lymphoid aggregates) (61,64).…”