Abstract A055: Lineage–tracing reveals a unique contribution of embryonic macrophages to NSCLC progression

Macrophages are the professional phagocytes of the innate immune system required to remove cellular debris and maintain tissue homeostasis. However, they can also play a role in the pathophysiology of many diseases. In non-small-cell lung carcinoma (NSCLC), macrophages constitute one of the major leukocyte subsets founds in tumors and contribute to immunosuppression by releasing growth factors, inhibiting immune T-cell surveillance, and enhancing angiogenesis, among other mechanisms. Importantly, macrophages in the lung can arise from embryonic or from adult hematopoietic precursors derived from the bone marrow (BM). This dual source of phagocytes has long been ignored and their contribution to tumor progression and response to immunotherapy has remained largely unexplored. Here we propose to analyze the role of macrophages during early and late stages of NSCLC. Using lineage-tracing murine models, tumor spheroids, and high-dimensional techniques to capture macrophage heterogeneity within the lesions (scRNAseq), we found that embryonic macrophages are progressively excluded from the tumor mass, whereas BM-derived ones are evenly distributed. Depletion of embryonic macrophages in a pretumor implantation setting diminishes tumor size and metastasis and leads to an increase in T-cell infiltration and antitumor activity, whereas elimination of tissue-resident macrophages post-tumor implantation does not impact tumor burden or immunity. Importantly, early human NSCLC lesions (stage I) show reduced macrophage infiltrates within the tumor microenvironment, which correlate with poor T-cell infiltration. Our findings suggest that macrophage ontogeny plays a pivotal role in tumor immunity. In this context, we aim to develop novel immunotherapies that harness embryonic macrophages to prevent tumor progression during early phases of lung cancer. Citation Format: Maria Casanova. Lineage–tracing reveals a unique contribution of embryonic macrophages to NSCLC progression [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A055.