Gong Qinyuan, Xu Rongzhen
Department of Hematology and Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Institute of Hematology, Zhejiang University, Hangzhou, China.
Front Immunol. 2025 Jan 9;15:1533740. doi: 10.3389/fimmu.2024.1533740. eCollection 2024.
Immune dysfunction is one of the hallmarks 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 human endogenous retrovirus K102 envelope (HERV-K102-Env) with immunosuppressive activity in circulating blood as a novel serum immunosuppressive biomarker of cancer. We first generated monoclonal antibodies against K102-Env with high sensitivity and specificity, and we developed an ELISA assay to detect serum K102-Env. We then investigated whether K102-Env and K108-Env proteins are present in circulating blood of cancer patients. We found K108-Env proteins were present in serum of both patients with cancer and healthy individuals. In contrast, K102-Env markedly increased in patients with PDAC, hepatocellular carcinoma (HCC), and non-small cell lung cancer (NSCLC) compared with healthy controls. 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 the sera of PDAC patients, K102-Env was 36.63-fold higher than that 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. These findings indicate that circulating K102-Env protein is a novel serum biomarker for evaluating immunosuppressive status and disease stage of patients with cancer.
免疫功能障碍是癌症的标志之一，在免疫治疗耐药中起关键作用，但目前尚无可用于评估癌症患者免疫功能障碍状态的血清生物标志物。在此，我们鉴定出循环血液中具有免疫抑制活性的亚型特异性人类内源性逆转录病毒K102包膜（HERV-K102-Env），作为一种新型的癌症血清免疫抑制生物标志物。我们首先制备了针对K102-Env的高灵敏度和特异性单克隆抗体，并开发了一种酶联免疫吸附测定（ELISA）法来检测血清中的K102-Env。然后，我们研究了K102-Env和K108-Env蛋白是否存在于癌症患者的循环血液中。我们发现K108-Env蛋白存在于癌症患者和健康个体的血清中。相比之下，与健康对照组相比，胰腺癌（PDAC）、肝细胞癌（HCC）和非小细胞肺癌（NSCLC）患者的K102-Env显著增加。PDAC、HCC和NSCLC患者中K102-Env的阳性率分别为34.00%、39%和28.0%，而只有5.0%的健康个体K102-Env略有升高。在PDAC患者的血清中，K102-Env比健康对照组高36.63倍。K102-Env显著上调T细胞的PD-1/PD-L1和c-Myc表达水平。重要的是，血清K102-Env水平与晚期癌症以及肿瘤生物标志物CA19-9和甲胎蛋白（AFP）密切相关。这些发现表明，循环中的K102-Env蛋白是一种用于评估癌症患者免疫抑制状态和疾病分期的新型血清生物标志物。
