DNA damage measurements as a potential biomarker for immunotherapy response in ovarian cancer.

Abstract

e17600 Background: Ovarian cancer patient outcomes are linked with DNA repair defects and damage within the tumor. In this study, we tested the Repair Assisted Damage Detection (RADD) assay, an emerging tool for measuring DNA damage, to identify tumors with more immunogenic landscapes that would benefit from immunotherapies. Methods: A cohort of 32 paired pre- and post-neoadjuvant chemotherapy (NACT) patient tumors were retrieved from the archival records at the University of Alabama at Birmingham (UAB). Patients were diagnosed with stage III or IV high-grade serous or endometrioid ovarian cancer. Samples came from an initial biopsy or laparoscopic debulking before receiving NACT (labeled as pre-NACT), matched with samples taken at the end of 3-4 NACT cycles (labeled as post-NACT). The RADD assay was performed on these samples, followed by gene expression analysis on a subset of pre-NACT samples to identify tumor immune signatures. Results: RADD scores for a broad spectrum of DNA lesions in the pre- and post-NACT samples showed higher levels of DNA damage following neoadjuvant chemotherapy. Examining the pre-NACT DNA damage levels, we also observed higher DNA damage levels in tumors that recurred after NACT. Comparison of immune signatures, using the Nanostring Pan I/0 360 panel, within the high and low DNA damage pre-NACT tumors showed indoleamine 2,3-dioxygenase 1 (IDO1) levels declined with higher RADD scores, suggesting high DNA damage levels result in less adaptive immune responses. We then specifically examined oxidative lesions within this cohort and saw a more significant correlation between high levels of oxidative DNA lesions and recurrence. We also observed decreased recurrence free survival for tumors with high levels of oxidative lesions. Immune signature analysis using the oxidative lesion scores identified myeloid, and TGFβ signatures decreased in high oxidative damage tumors, suggesting high damage levels alter adaptive immune responses. Conclusions: The broad-spectrum DNA damage analysis showed NACT increased DNA damage levels within tumors, showing the potential of RADD for monitoring treatment response, and guiding targeted therapies. The lesion-specific analysis showed that DNA damage type influences the tumor microenvironment and recurrence. Importantly, this work links DNA lesions within tumors with immune environment changes and suggests that DNA damage may indicate the susceptibility of a tumor to immunotherapy.