Anlotinib Combined with Anti-PD1 Potentiates Anti-Tumor Immunity via Immunogenic Cell Death and Macrophage Reprogramming

The combination therapy of targeted drugs and immune checkpoint inhibitors has shown prominent success. In addition to blocking mutated oncogene downstream signaling, the immunological mechanism(s) underlying the anti-tumor effect of targeted-immuno-therapy is not clear. In this study, anlotinib, a novel pan-targeted tyrosine kinase receptor inhibitor (pTKI), is combined with anti-PD1 (& alpha;PD1) as a therapeutic regimen applying to an immunocompetent mouse tumor model. Anlotinib induces immunogenic cell death (ICD), elicits anti-tumor inflammation and infiltration, and activation of DCs and CD8(+) T cells, which are enhanced by & alpha;PD1. Furthermore, anlotinib reduces KC/MCP-1 secretion by attenuating educational effect that cancer cells imposed on tumor-associated macrophages (TAMs) and prevents their M2 polarization by inhibiting AKT/mTORC1 and Ppar & delta; pathways. Importantly, anlotinib plus & alpha;PD1 prolongs median progression-free survival time compared with standard chemotherapy plus pembrolizumab as the 1(st) line treatment in non-small cell lung cancer (NSCLC) patients. Thus, anlotinib treatment elicits both innate and adaptive anti-tumor immune responses while & alpha;PD1 enhances its potency. This study provides strong evidence that combination of targeted therapy and immunotherapy is a promising regimen for treating NSCLC.