Abstract 6096: Targeting premalignant lung cancer to intercept progression to invasive disease

Abstract Increased implementation of low dose CT-guided screens in the clinic has led to the identification of premalignant lung nodules (ground glass opacity, GGO) which progress to invasive adenocarcinoma1,2. Using integrated genomic analysis of a cohort of >300 patients with premalignant lesions, we constructed the first high-resolution landscape of composition, lineage/functional states, developmental trajectories, and multicellular crosstalk networks, which revealed potential targets for therapeutic intervention. We uncovered that early lesions exhibit marked immune-suppressive phenotypes characterized by increased T lymphocyte exhaustion to cytotoxic scores, decrease in NKT cells, elevated Tregs, increased myeloid suppressor activity, accumulation of immunosuppressive myeloid cells activation of unfolded protein response (UPR) sensor IRE1α that activates the multitasking transcription factor XBP1 known to drive malignant progression. Targeting IRE1α endoribouclease with a small molecule drug limited disease progression with marked immunomodulation in our newly developed Kras and EGFR driven mouse models, which mirror progression of human precursor lesions to invasive disease. As an immunoprevention approach, we have generated LNP-mRNA vaccines targeting top two shared neoantigens in premalignant lesions, which have shown marked immunogenicity and efficacy in early disease. Our work provides the molecular foundation for precision oncology strategies to intercept transition of preinvasive to invasive adenocarcinoma. 1. Altorki, N.K., et al. Nat Rev Cancer, 2019. 2. Altorki, N.K., et al. Cell Rep, 2022. Citation Format: Mitchell Martin, Yongfeng He, Bhavneet Bhinder, Liron Yoffe, Sijin Luo Zhong, Arshdeep Singh, Olivier Elemento, Shaoyi Jiang, Nasser Altorki, Vivek Mittal. Targeting premalignant lung cancer to intercept progression to invasive disease [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(6_Suppl):Abstract nr 6096.