Abstract 1207: The evolution of immunity and immune evasion from early- to end-stage lung cancer

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Abstract Deciphering the changes in the tumor and tumor microenvironment (TME) that accompany metastatic disease progression is essential if we are to identify potential new anti-cancer treatments. In particular, a complete understanding of how cancer subclones and TME evolve over time from primary disease to death, both independently and in relation to one another, and of the impact of therapies such as immunotherapy (IO) on TME composition and architecture, remain lacking. In this work, we sought to profile the changes in both cancer-cell intrinsic genomic immune evasion and TME that accompany lung cancer progression from diagnosis to death. To do this, we applied multiple orthogonal methods (whole-exome sequencing; RNAseq; imaging mass cytometry) to >500 longitudinally collected primary, pre-mortem metastatic, and postmortem metastatic tumor samples from 23 patients with non-small cell lung cancer (NSCLC) co-recruited to the UK national TRACERx (TRAcking Cancer Evolution through therapy [Rx], NCT01888601) and PEACE (Posthumous Evaluation of Advanced Cancer Environment) autopsy studies. Samples covered multiple organ sites and were derived from both patients who did and did not receive IO, allowing analysis of the differential impact of treatment on end-stage disease profiles. Sequencing analyses suggest that heterogeneous mechanisms of immune evasion develop at distinct metastatic sites, and between metastases and the primary tumor. Profiling of TME indicated a global reduction in immune cell densities in metastatic compared to primary tumor samples and a skewing towards cytotoxic and terminally differentiated CD8 T cell subtypes. Previous work had identified four major TME architectures in primary NSCLC, based on the abundance and location of tumor infiltrating lymphocytes, macrophages and neutrophils, including a neutrophil-rich TME found to be associated with metastasis. In this work, we identified new TME classes found in metastatic samples, including those dominated by myeloid cells in the stroma. Two new TME classes, predominantly comprised of post-mortem metastatic samples from IO-treated patients, were significantly enriched in tumor-infiltrating cytotoxic CD8 T cells compared to other classes. TMEs of regions within the same metastasis were found to be more similar to each other than to those of primary tumor regions. Using computational approaches to track cancer subclones, we reconstructed metastatic migration histories for each patient and found that the TMEs of source and target metastases in a met-met migration pair were more similar than those from pairs of metastases from the same patient without a direct migration path. Our findings provide insights into the relationships between genetic immune evasion and immune cell infiltration across the lung cancer disease course. Citation Format: Sonya Hessey, Mihaela Angelova, Emma Colliver, Katey S. Enfield, Kerstin Haase, Michelle M. Leung, Corentin Richard, Robert Bentham, Clare Puttick, Oriol Pich, Wing Kin Liu, Alastair Magness, Abigail Bunkum, Kristiana Grigoriadis, Ariana Huebner, David A. Moore, Monica Sivakumar, Roberto Salgado, Philip S. Hobson, Dina Levi, Sophia Ward, Selvaraju Veeriah, Cristina Naceur-Lombardelli, Andrew Rowan, Crispin T. Hiley, Simone Zaccaria, Nicholas McGranahan, Charles Swanton, Mariam Jamal-Hanjani. The evolution of immunity and immune evasion from early- to end-stage lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1207.

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