Subtype-specific HERV-K102 envelope is a novel serum immunosuppressive biomarker and therapeutic target of cancer

Abstract

Background: Immune dysfunction is a hallmark of cancer and plays critical roles in immunotherapy resistance, but there is no serum biomarker that can be used to evaluate immune-dysfunction status of cancer patients. Here, we identified subtype-specific HERV-K102 envelope (K102-Env) with immunosuppressive activity in circulating blood as a novel serum immunosuppressive biomarker of cancer. Methods: We first generated monoclonal antibodies against K102-Env with high sensitivity and specificity, and we developed an ELISA assay for serum K102-Env. We then investigated whether K102-Env and K108-Env proteins are present in circulating blood of cancer patients. Results: We detected K108-Env in 63.33% of patients with pancreatic duct adenocarcinoma (PDAC) (n = 30) and 63% of healthy sera (n = 30). In contrast, K102-Env markedly increased in patients with PDAC, hepatocellular carcinoma (HCC), and non-small cell lung cancer (NSCLC) compared with healthy controls (p < 0.01). The positive rates of K102-Env were 34.00%, 39%, and 28.0% in PDAC, HCC, and NSCLC, respectively, whereas only 5.0% of healthy individuals had marginally increased K102-Env. In patients with PDAC, K102-Env was 36.63-fold higher than in sera of healthy controls. K102-Env significantly upregulated PD-1/PD-L1 and c-Myc expression levels of T cells. Importantly, serum K102-Env levels correlated well with advanced cancers and tumor biomarkers CA19-9 and AFP. Conclusion: These findings indicate that circulating K102-Env is a novel serum biomarker for evaluating immunosuppressive status and disease stage of patients with cancer, and it also provides a potential target for cancer immunotherapy.