Correlation of HERVK with efficacy on anti-PD-1/PD-L1 therapy in a pilot metagenomics study on Chinese advanced lung cancer patients.

Abstract

e14046 Background: Patient selection for PD-1 inhibitors in NSCLC is still based on imperfect screening biomarkers, including PD-L1 expression and tumor mutational burden(TMB).There are several reports show certain bacteria or virus infections are correlated with efficacy and prognosis on PD-1 inhibitors treatment. In order to explore more potential biomarkers for anti-PD-1 therapy, we investigate whether we can discover microorganisms in Chinese lung cancer patients and whether certain microorganism are correlated with efficacy or prognosis on anti-PD-1 therapy using metagenomics technology. Methods: In this study, 30 advanced lung cancer patient were enrolled, including 15 cases of adenocarcinoma, 12 cases of squamous carcinoma, 2 cases of Small cell lung cancer. 10 patients received PD-1/PD-L1 inhibitors as first-line therapy and other patients as second-line therapy. Among these 30 patients, 15 PR,1 CR, 10 PD, 4 SD according to RECIST 1.1. Plasma cell-free DNA (cfDNA) were collected from these patients prior to anti-PD-1 treatment and whole-genome sequencing of cfDNA at average coverage 5X was performed on Illumina NovaSeq in 2 ×150bp length model. A bioinformatics pipeline composed of 4 tools: BWA/Sambama/Kraken2/Bracken, was constructed to analyze the sequencing data. Non-human derived reads were extracted by sambama from the bam file that generated by BWA. Bacteria/Virus abundance in each sample was estimated through Bracken, followed by bac/vir database alignment in Kraken2. Results: In our pilot study, 4 patients were selected for metagenomics sequencing(1CR, 1PR, 2PD). Interestingly, over 100 different microbial sequence were detected in every patient. Compare microorganism in CR+PR patients to PD patients, Human endogenous retrovirus K (HERVK) were quite abundant in CR/PR patients but not in PD patients: 5.6 times more abundant in CR/PR patients comparing to PD patients. (HERVK abundance: CR:PR:PD = 1.20% : 0.32% : (0.17%, 0.10%)). HERVK is a family of human endogenous retroviruses associated with certain malignant tumors, studies have indicated that HERVK may trigger an antigen specific immune response for certain cancer patients. Conclusions: Metagenomics sequencing on plasma cfDNA could be a potential biomarker discovery approach to identify prognostic biomarkers for anti-PD-1 therapy. HERVK are correlated with efficacy on anti-PD-1 treatment in our pilot study, however more thorough investigation need to be conducted to confirm whether HERVK can be served as efficacy biomarkers for anti-PD-1.