Abstract 3436: Emerging evidence of cellular dormancy programs in non-small cell lung cancer (NSCLC)

Abstract Despite the practice-changing incorporation of neoadjuvant chemoimmunotherapy (nCI) into the management of clinical stage II-III NSCLC, lung cancer recurrence remains a clinical challenge. At our institution, long-term follow-up has revealed individuals with evidence of recurrence after curative-intent therapy despite demonstrating initial response to nICI and surgery. One potential explanation is cellular dormancy, a state of reversible growth arrest characterized by reduced metabolism and therapeutic resistance, a process well described in breast and head and neck cancers. To investigate lung cancer dormancy, our group has begun collecting lung tumor bed tissue from resected NSCLC patients following nCI. Using these tissues and downstream patient derived organoid (PDO) generation as our primary model, we aimed to characterize dormancy associated gene expression in NSCLC and determine whether chemotherapy and/or immunotherapy induce these programs. We used complementary approaches to address this question. First, to investigate the impact of nCI on tumor heterogeneity and dormancy programs, single-cell Assay for Transposase-Accessible Chromatin (scATAC) sequencing was performed on surgically resected clinical stage II-III NSCLC specimens representing a range of responses to nCI (untreated, 50%, 85%, and 100% regression). We examined gene activity scores across these samples using chromatin accessibility. Our analyses indicated that untreated patient samples exhibited known intratumoral heterogeneity, including cell states with chromatin features similar to alveolar differentiation intermediates, which have been observed as important precursors to lung cancer evolution. Additionally, scATAC-seq from four resected tumors revealed a distinct EPCAM-positive cell population with high gene scores for numerous known cellular dormancy markers, including NR2F1, BHLHE41, SOX9, SOX2, p21, p27, and RARβ. These cells were enriched in untreated samples, suggesting a pre-existing dormant-like subpopulation, but were also present in tumors across all nICI response categories, suggesting the persistence or induction of dormancy following treatment. In parallel, we examined the expression of canonical dormancy markers using quantitative polymerase chain reaction (qPCR), which demonstrated that Cisplatin exposure to PDOs increased the expression of NR2F1, SOX9, p21, and p27 and decreased Ki67, consistent with treatment-induced dormancy. These studies serve as the foundation for dormancy modeling in NSCLC PDOs. Ongoing efforts include cytokine profiling of patient blood samples with the goal of identifying inflammatory signatures that distinguish complete responders from partial responders to nICI. Citation Format: Grace Ha, Melissa Tracy, Anthony Griffen, Daniel Bravo, Dior Dedushi, Terence Li, David Schecter, Neel Chudgar, Chaoyuan Kuang, Julio Aguirre-Ghiso, Brendon Stiles, Lindsay M. LaFave. Emerging evidence of cellular dormancy programs in non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3436.