Therapeutic Targeting of Macrophage Plasticity Remodels the Tumor-Immune Microenvironment

Although the majority of patients with advanced lung adenocarcinoma (LUAD) are eligible to receive immune checkpoint blockade, approximately 80% of these tumors are resistant to this therapeutic approach. Insights at the single-cell level into mechanisms that drive LUAD tumorigenesis and the relationcheckpoint blockade could help identify biomarkers and potencacy. Here, we used a genetically engineered mouse model that replicates the development of human LUAD through a spectrum of preinvasive to invasive adenocarcinoma histologic subtypes. A systems onco-immunology approach of integrating the analytical power and unique, complementary capabilities of time-offlight mass cytometry (CyTOF) and imaging mass cytometry was leveraged to identify cellular and spatial immune contextures in LUAD. Comprehensive investigation of mouse and human LUAD using these single-cell proteomics platforms showed that LUAD progression is associated with spatiotemporal evolution of tumor-associated macrophages in the tumor-immune micro-environment, which governs tumor response to immunotherapy. PD-1 was expressed in a highly plastic tumor-promoting subtype of tumor-associated macrophages that develops during tumor progression from preinvasive to invasive adenocarcinoma, controls the lymphocyte-depleted niche of invasive tumors, and protects tumor cells in the solid histologic components of the tumor. Longitudinal, multidimensional single-cell analyses of LUAD tumorigenesis revealed dynamic alteration of immunoregulatory PD-1-expressing tumor-associated macrophages that can be targeted to overcome resistance to checkpoint immunotherapy. Significance: Comprehensive single-cell proteomics analyses of lung adenocarcinoma progression reveal the role of tumor-associated macrophages in resistance to PD-1 blockade therapy. See related commentary by Lee et al., p. 2515