Identification of an endogenous retroviral signature to predict anti-PD1 response in advanced clear cell renal cell carcinoma: an integrated analysis of three clinical trials

Ther Adv Med Oncol. 2022 Sep 24:14:17588359221126154. doi: 10.1177/17588359221126154. eCollection 2022.

Authors

Jian-Guo Zhou¹, Yu Zeng², Haitao Wang³, Su-Han Jin⁴, Yun-Jia Wang⁵, Sisi He⁵, Benjamin Frey⁶, Rainer Fietkau⁷, Markus Hecht⁷, Hu Ma⁸, Wenchuan Zhang⁹, Udo S Gaipl¹⁰

Affiliations

¹ Department of Oncology, The second affiliated Hospital of Zunyi Medical University, Zunyi, China Translational Radiobiology, Department of Radiation Oncology, Universitätsklinikum Erlangen, Erlangen, GermanyDepartment of Radiation Oncology, Universitätsklinikum Erlangen, Erlangen, Germany Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany.
² Department of Neurosurgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
³ Thoracic Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
⁴ Department of Orthodontic, School of Stomatology, Zunyi Medical University, Zunyi, China.
⁵ Department of Oncology, The second affiliated Hospital of Zunyi Medical University, Zunyi, China.
⁶ Translational Radiobiology, Department of Radiation Oncology, Universitätsklinikum Erlangen, Erlangen, GermanyDepartment of Radiation Oncology, Universitätsklinikum Erlangen, Erlangen, Germany Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany.
⁷ Department of Radiation Oncology, Universitätsklinikum Erlangen, Erlangen, Germany Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany.
⁸ Director of Department of Oncology, Vice President of the second affiliated Hospital of Zunyi Medical University, Intersection of Xinlong And Xinpu Avenue, Zunyi, 563000, China.
⁹ Director of Department of Neurosurgery, Department of Neurosurgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai, 200011, China.
¹⁰ Head of Translational Radiobiology, Department of Radiation Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Universitätsstraße 27, Erlangen, 91054, Germany.Department of Radiation Oncology, Universitätsklinikum Erlangen, Erlangen, Germany. Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany.

Abstract

Background: Endogenous retrovirus (ERV) elements are genomic footprints of ancestral retroviral infections within the human genome. Previous studies have demonstrated that dysregulated ERV transcription level is associated with immune cell infiltration in cancers, but the association between ERV expression and programmed cell death protein 1 (PD-1) blockade response is currently unraveled for solid cancers, such as advanced clear cell renal cell carcinoma (ccRCC).

Methods: ERV mRNA profiles were obtained from three clinical trials of ccRCC where the patients were treated with anti-PD-1 (CM-009, CM-010, CM-025, and TCGA-KIRC data). Patients treated with nivolumab were divided into training and test cohort, while the TCGA-KIRC cohort was used as an external validation. Univariate Cox regression analysis and least absolute shrinkage and selection operator regression were used to establish the signature. Immune cell infiltration analysis and gene set enrichment analysis were performed to explore potential biological mechanisms.

Results: An ERV signature was established based on nine ERV expression patterns. In the training cohort, the median overall survival in the low- and high-risk group was 45.2 and 19.6 months [hazard ratio (HR) = 0.49, 0.32-0.75, p < 0.001], respectively. The results were confirmed in the test (HR = 0.41, 0.20-0.83, p = 0.013), and in the TCGA-KIRC cohort (HR = 0.55, 0.34-0.90, p = 0.017). Moreover, in the CM-025 cohort, the low-risk group that received nivolumab had a more favorable survival compared with those that received the mTOR inhibitor everolimus, while no significant differences were observed in the high-risk group. CD8+ T cells were enriched in the low-risk group, while immune suppressive pathways were suppressed.

Conclusion: The newly identified ERV signature is not only a prognostic, but also a predictive biomarker for advanced ccRCC patients who received anti-PD-1 therapy, which can guide personalized treatment in cancer patients in the future.

Keywords: ERV; ccRCC; nivolumab; predictive; prognostic.