Biological and clinical significance of spatial immune heterogenenity in non-small cell lung cancer

The spatial tumor microenvironment heterogeneity is considered as a hallmark of cancer and a main driver of disease progression and therapeutic resistance. The spatial positioning of tumor infiltrating lymphocytes (TILs) can reflect the capacity of the adaptive immune system to fight cancer, and the presence of a non-uniform or spatially heterogeneous T-cell response could limit tumor elimination and favor clonal selection. B-cells can also mount antigen specific responses, are involved in cancer rejection, and commonly form nodular aggregates within the TME known as tertiary lymphoid structures (TLS) that have been recognized as critical to the establishment of productive anti-tumor immunity and immunotherapy responses. Although spatial tumor heterogeneity has been recognized as a key feature of cancer and identified in most solid malignancies, including non-small cell lung cancer (NSCLC), little is known about its properties, and it is not being considered or used clinically. Possible reasons explaining why progress has been limited in understanding intratumor spatial heterogeneity include the paucity of suitable experimental models and the lack of standardized metrics to measure it. In this project, we hypothesize that the spatial TIL heterogeneity (STH) is a measurable biological determinant of disease progression and sensitivity/resistance to anti-cancer immunotherapy in human NSCLC. We will address this hypothesis through 2 independent aims with complementary aspects and prominent integrative potential: Aim 1 will elucidate the biological and clinical significance of the STH in NSCLC; and Aim 2 will analyze the impact of anti-cancer therapies on the spatial immune heterogeneity in NSCLC. The results from this project will expand our understanding of the biological determinants and significance of spatial immune heterogeneity in NSCLC and could open new avenues for the development of clinically relevant biomarkers or novel anti-cancer therapeutics. Project Number: 1R21CA297430-01 | Fiscal Year: 2025 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Kurt Schalper | Institution: YALE UNIVERSITY, NEW HAVEN, CT | Award Amount: $478,532 | Activity Code: R21 | Study Section: Molecular Cancer Diagnosis and Classification Study Section[MCDC] View on NIH RePORTER: https://reporter.nih.gov/project-details/11036917