Anlotinib optimizes anti-tumor innate immunity to potentiate the therapeutic effect of PD-1 blockade in lung cancer

• Published in: Cancer Immunology, Immunotherapy Immunotherapy, 2020-12, Vol.69 (12), p.2523-2532
• Main Authors: Yang, Yinli, Li, Ling, Jiang, Zhansheng, Wang, Bin, Pan, Zhanyu
• Format: Article
• Language: English
• Subjects: Adenomatous polyposis coli; Angiogenesis; Animals; Antiangiogenic agents; Antigen-presenting cells; Antineoplastic Agents, Immunological - pharmacology; Antineoplastic Agents, Immunological - therapeutic use; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Apoptosis; B7-H1 Antigen - antagonists & inhibitors; B7-H1 Antigen - immunology; Cancer Research; Carcinoma, Lewis Lung - drug therapy; Carcinoma, Lewis Lung - immunology; Carcinoma, Lewis Lung - pathology; Cell death; Cell Line, Tumor; Clinical trials; Dendritic cells; Dendritic Cells - drug effects; Dendritic Cells - immunology; Drug Synergism; Female; Immune checkpoint inhibitors; Immunity, Innate - drug effects; Immunology; Immunoregulation; Immunotherapy; Indoles - pharmacology; Indoles - therapeutic use; Innate immunity; Killer Cells, Natural - drug effects; Killer Cells, Natural - immunology; Lung cancer; Macrophages; Macrophages - drug effects; Macrophages - immunology; Medicine; Medicine & Public Health; Metastases; Mice; Natural killer cells; Non-small cell lung carcinoma; Oncology; Original; Original Article; PD-1 protein; PD-L1 protein; Programmed Cell Death 1 Receptor - antagonists & inhibitors; Programmed Cell Death 1 Receptor - immunology; Quinolines - pharmacology; Quinolines - therapeutic use; Small cell lung carcinoma; Tumor Microenvironment - drug effects; Tumor Microenvironment - immunology
• ISSN: 0340-7004; 1432-0851
• DOI: 10.1007/s00262-020-02641-5

Background Many anti-angiogenic agents have the potential to modulate the tumor microenvironment and improve immunotherapy. Anlotinib has demonstrated anti-tumor efficacy in non-small cell lung cancer (NSCLC) in third-line clinical trials. However, its roles in immune regulation and potentially synergistic anti-tumor effect in combination with immune checkpoint inhibition remain unclear. Methods Here, based on a syngeneic lung cancer mouse model, the intratumoral immunological changes post-anlotinib treatment in the model were assessed. Furthermore, it was tested whether anlotinib could enhance the anti-tumor effect of αPD-1 in vivo. Results This study shows that anlotinib increased infiltration of the innate immune cells, including natural killer (NK) cells, and antigen-presenting cells (APC), which include M1-like tumor-associated macrophages (TAM) and dendritic cells (DC), whereas the percentage of M2-like TAM was dramatically reduced. Subsequently, when combined with PD-1/PD-L1 (programmed cell death 1/PD-1 ligand 1) blockade, anlotinib conferred significantly synergistic therapeutic benefits. Conclusions Overall, these findings describe a role for anlotinib in the innate immune cells in the tumor microenvironment and a potentially synergistic anti-tumor combination with immune checkpoint inhibition.