Abstract 2753: Deciphering macrophage function in lung tumor microenvironment and disease progression

Abstract

Abstract Introduction: Lung cancer is the leading cause of cancer-related mortality, with non-small cell lung cancer (NSCLC) as the most common form. Targeting the immune system with immune checkpoint inhibitors has transformed NSCLC treatment, highlighting the crucial contribution of immune cells and the tumor microenvironment (TME) to NSCLC initiation and progression. However, oncogenic-driven cancers treated with targeted molecular therapies have not benefited from immunotherapy, suggesting that other mechanisms of disease progression and resistance are involved. Macrophages in the lung TME are associated with disease outcomes but their exact role in tumor progression and resistance is less well understood. Characterizing their function using high-resolution methods, such as single cell RNA sequencing (scRNAseq), has the potential to identify mechanisms by which macrophages promote lung cancer progression and drug resistance. Methods: We performed scRNAseq analyses on individual human NSCLC tumor biopsies collected at different treatment states. Samples were obtained from patients before initiating systemic targeted therapy (treatment-naïve, TN), at the residual disease state, which includes samples taken at any time during treatment with targeted therapy while the tumor was regressing or at a stable state by standard clinical imaging (residual disease, RD), and upon the subsequent and clear progressive disease, as determined by standard clinical imaging, at which point the tumors had establishment of acquired drug resistance (progressive disease, PD). Samples were primarily EGFR-, BRAF-, and ALK-driven tumors. Macrophages from lung tumor biopsies were identified and annotated using SingleR, which is a computational method for unbiased cell type recognition of scRNAseq, and then characterized. Results: We identified 678 macrophages that clustered into 7 distinct groups (Figure 1A). Clusters MF0, MF1, MF3, and MF5 had significant differences across treatment time points. Cluster MF0 had significantly less RD cells and was characterized by expression of genes associated with neutrophil and leukocyte recruitment. Cluster MF5 had significantly more PD cells and was characterized by expression of genes associated with T-cell activation (Figures 1B and 1C). Conclusion: We annotated macrophages in the lung TME using scRNAseq and characterized macrophage changes across different treatment states. Our findings suggest there are less macrophages recruiting neutrophils and leukocytes in RD compared to TN and PD, and more T-cell activating macrophages in PD compared to TN and RD, which could have potential therapeutic and prognostic implications. Citation Format: Elizabeth A. Yu, Wei Wu, Philippe Gui, Caroline E. McCoach, Collin M. Blakely, Stephanie A. Christenson, Trever G. Bivona. Deciphering macrophage function in lung tumor microenvironment and disease progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2753.