Abstract 1609: Inferring the T cell repertoire dynamics in non-small cell lung cancer metastases

Abstract

Abstract Non-small cell lung cancer (NSCLC) is a highly complex disease, characterized by extensive genomic heterogeneity and dynamic evolution under therapeutic pressure. This evolution can lead to alterations in the antigens expressed by cancer cells, thereby influencing the T cell repertoire (TCR) as T cells expand in response to foreign antigens. Despite the central role of TCR in cancer progression and treatment response, only few studies have investigated the temporal and spatial changes in the TCR repertoire. In this study, we delve into the role of the TCR repertoire in metastatic progression in NSCLC. We conducted TCR sequencing of multiregion primary tumors, normal-adjacent tissues, and post-mortem metastases sampled from a cohort of 22 patients enrolled in the TRACERx and PEACE studies. Our findings reveal that primary tumor regions and normal-adjacent tissues exhibit similar fractions of expanded clonotypes. However, a higher proportion of expanded intratumoral TCRs were privately expanded in the tumor samples, suggesting a unique TCR landscape within the tumor microenvironment. The TCR repertoire across multiregion primary tumor samples was largely homogenous, with most expanded clonotypes shared across at least two regions. However, only a small fraction of these clonotypes were tracked in metastases, indicating a significant shift in the TCR repertoire during metastatic progression. Notably, the expanded clonotypes that persisted over time from early to late stage disease were significantly enriched for clonotypes ubiquitously expanded in the primary tumor across all regions. This was not shown to be associated with an increased likelihood of generation via VDJ recombination, suggesting a tumor-specific immune response. The expanded TCR repertoire in the postmortem metastases clustered mainly by anatomical site, suggesting an immune response driven by tissue-resident T cells. Moreover, we found a significant positive correlation between repertoire dissimilarity and genomic distance, suggesting that T cell clones track with tumor clones across spatial sites within patients. Our study demonstrates the significant spatiotemporal dynamics of the TCR repertoire during the metastatic progression of NSCLC, orchestrated by both tissue-resident T cells and the genomic evolutionary trajectory of tumors. Such an exploration could provide valuable insights to inform future strategies for immunotherapy treatments and enhance clinical monitoring of patients. Citation Format: Corentin Richard, Sonya Hessey, Cristina Naceur-Lombardelli, Selvaraju Veeriah, Gayathri Nageswaran, Crispin Hiley, Sergio Quezada, Benny Chain, TRACERx and PEACE Consortia, Charles Swanton, Mariam Jamal-Hanjani. Inferring the T cell repertoire dynamics in non-small cell lung cancer metastases [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 1609.