Abstract 4670: The expression of HERV-K subfamilies indicated improved prognosis in small cell lung cancer

Abstract Background: The abnormal activation of human endogenous retroviruses (HERV) in tumor tissues has been proven implicated in cancer development and progression. Prior research demonstrated that antibodies against the HERV-K envelope protein could be produced by B cells in non-small cell lung cancer (NSCLC), enhancing immunotherapy efficacy. However, the role of HERV-K in small cell lung cancer (SCLC) remains largely unexplored. Methods: Bulk RNA sequencing data from the IMpower-133 cohort (n = 271) was analyzed to detect the expression of HERV transcripts using the TELESCOPE algorithm. Single-cell RNA sequencing data from SCLC patients (n = 20) were employed for cell annotation. Carcinoma ecotypes (CEs) and cell-type proportions in SCLC were identified using EcoTyper, CIBERSORTx, and BayesPrism software. Immunohistochemistry (IHC) was performed to validate HERV-K expression in tumor samples collected at Peking University People’s Hospital (n = 48). Kaplan-Meier survival analysis and multivariable Cox regression were used to evaluate clinical outcomes. Results: By applying TELESCOPE in IMpower-133 dataset, we detected the expression of 468 HERV subfamilies and depicting the landscape of HERV subfamilies in SCLC. Survival analyses revealed that high expression of HML-2 (HERV-K), HERV-K11, and HERV-K13 subfamilies was associated with prolonged overall survival. Using CIBERSORTx and EcoTyper, bulk RNA sequencing data from IMpower-133 was deconvoluted into cell types, and five carcinoma ecotypes (CEs) were identified based on the co-occurrence of cell states. Notably, high expression of ERVK7, a locus-specific transcript of the HML-2 subfamily, was significantly correlated with higher abundance of CE1 across all samples (r = 0.43, p < 0.0001). CE1, the most prevalent ecotype in SCLC, was primarily composed of macrophages, CD38+ CD8+ T cells, CD4+ T cells, mature B cells, and plasma cells. CE1 abundance was associated with improved progression-free survival in SCLC patients receiving chemotherapy, as supported by multivariable Cox regression (HR = 0.32, CI: 0.13-0.77, p = 0.011). This finding was consistent with progression-free survival analysis based on ERVK7 expression (p = 0.036). The association between ERVK7 and macrophages was further validated through deconvolution of single-cell RNA sequencing data from SCLC using BayesPrism. Additionally, IHC of SCLC patient tumor samples confirmed HERV-K envelope protein (27/48) and ERVK7 (5/8) expression in tumor tissue. Higher HERV-K envelope protein expression was also associated with better disease-free survival, as supported by Kaplan-Meier analysis (p = 0.028). Conclusions: The elevated expression of HERV-K indicated the better prognosis of SCLC patients, potentially due to the immune-hot tumor environment. These findings suggest that HERV-K may serve as potential biomarkers or co-stimulatory therapeutic targets for SCLC immunotherapy. Citation Format: Xingyuan Wu, Jingwei Zhang, Yan Ju, Xiao Li. The expression of HERV-K subfamilies indicated improved prognosis in small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4670.