Overcoming Microenvironmental Resistance to PD-1 Blockade in Genetically Engineered Lung Cancer Models.

Lung cancer resistance to PD-1 inhibition can be overcome by targeting tumor-associated macrophages in mouse models. Targeting TAMs Antiangiogenic drugs may improve the efficacy of immune checkpoint blockade (ICB) in patients with cancer, but the determinants of tumor response have not been elucidated. Martinez-Usatorre and colleagues studied tumor resistance to combinations of ICB, antiangiogenic therapy, and chemotherapy in mouse models of non–small cell lung cancer (NSCLC). They found that antiangiogenic treatment combined with ICB was not beneficial and even accelerated progression of some tumors. Antiangiogenic therapy increased tumor infiltration by PD-1+ regulatory T cells that were sustained by tumor-associated macrophages (TAMs). Depleting TAMs redirected PD-1 antibodies to CD8+ T cells to improve combination treatment efficacy, suggesting that macrophage depletion in combination with antiangiogenic immunotherapy should be studied in patients with NSCLC. Immune checkpoint blockade (ICB) with PD-1 or PD-L1 antibodies has been approved for the treatment of non–small cell lung cancer (NSCLC). However, only a minority of patients respond, and sustained remissions are rare. Both chemotherapy and antiangiogenic drugs may improve the efficacy of ICB in mouse tumor models and patients with cancer. Here, we used genetically engineered mouse models of KrasG12D/+;p53−/− NSCLC, including a mismatch repair–deficient variant (KrasG12D/+;p53−/−;Msh2−/−) with higher mutational burden, and longitudinal imaging to study tumor response and resistance to combinations of ICB, antiangiogenic therapy, and chemotherapy. Antiangiogenic blockade of vascular endothelial growth factor A and angiopoietin-2 markedly slowed progression of autochthonous lung tumors, but contrary to findings in other cancer types, addition of a PD-1 or PD-L1 antibody was not beneficial and even accelerated progression of a fraction of the tumors. We found that antiangiogenic treatment facilitated tumor infiltration by PD-1+ regulatory T cells (Tregs), which were more efficiently targeted by the PD-1 antibody than CD8+ T cells. Both tumor-associated macrophages (TAMs) of monocyte origin, which are colony-stimulating factor 1 receptor (CSF1R) dependent, and TAMs of alveolar origin, which are sensitive to cisplatin, contributed to establish a transforming growth factor–β–rich tumor microenvironment that supported PD-1+ Tregs. Dual TAM targeting with a combination of a CSF1R inhibitor and cisplatin abated Tregs, redirected the PD-1 antibody to CD8+ T cells, and improved the efficacy of antiangiogenic immunotherapy, achieving regression of most tumors.