Abstract 5028: Detection of non-small cell lung and bladder cancer signatures in peripheral blood using a novel antibody-free chromatin capture assay

Abstract Immune checkpoint inhibition (ICI) via anti-PD-1/PD-L1 has improved clinical outcomes for multiple cancers, including bladder and non-small cell lung cancer (NSCLC). Yet, the response rates remain low highlighting a significant knowledge gap in the mechanisms driving response and resistance. While the expression of PD-L1 has been established as a predictive biomarker of ICI response, other features, including molecular tumor burden, tumor microenvironment (TME), and the host’s immune mechanisms may contribute to overall response. The complex interactions between a tumor and the immune system underscore the need for a more comprehensive approach to explore novel biological and immunological insights of cancer progression. Circulating tumor DNA assays, while integral to contemporary decision-making in oncology, fall short in delineating the transcriptional programs that dictate cancer phenotypes and their evolution over the disease trajectory. To bridge this gap, we have developed a plasma-based active chromatin capture method that enables the comprehensive epigenetic and transcriptomic interrogation of both tumor and immune components. In this study, we quantified epigenetic profiles from plasma samples (n=100) of patients with bladder cancer (n=20) and NSCLC (n=24) undergoing ICI therapy, along with samples (n=70) from healthy individuals (n=5). As expected, the total cfDNA yield (ng) of lung (1. 7x, p=2. 3e-08) and bladder (1. 98x, p=1. 6e-11) cancer samples were higher than those of healthy individuals. More Interestingly, the longer cfDNA fragments derived from regulatory-active chromatin, also showed a significantly higher abundance in plasma samples from both lung (2. 0x, p=2. 5e-09) and bladder (3. 2x, p=3. 2e-14) cancer patients. Furthermore, the patterns of epigenetic regulations across cancer and healthy conditions showed distinct and stable clusters, consistent between gene bodies and transcription start sites, highlighting the epigenetic changes that may be driving cancer progression. We also observed a common enrichment of immune epigenetic signatures in both lung and bladder cancer samples, likely attributed to shared mechanisms associated with the modulation of the tumor microenvironment and immune interactions. Understanding these changes at an epigenetic level could provide insights into novel therapeutic approaches that target the tumor microenvironment and the immune interactions. Citation Format: Kevin Lai, Katharine Dilger, Rachael Cunningham, Timothy Barnes, Khiet Truong, Kathy Lam, Rhea Boquiren, Maggie C. Louie, Diana Abdueva. Detection of non-small cell lung and bladder cancer signatures in peripheral blood using a novel antibody-free chromatin capture assay abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 5028.