Tyrosine Kinase Inhibitor Cabozantinib Inhibits Murine Renal Cancer by Activating Innate and Adaptive Immunity
Hongyan Liu, Shishuo Sun, Gang Wang, Mengmeng Lü, Xiaokang Zhang, Xiaohuan Wei, Xiaoge Gao, Chao Huang, Zhen Li, Junnian Zheng, Qing Zhang
Abstract
Background Advanced renal cell carcinoma (RCC) has a very dismal prognosis. Cabozantinib, a tyrosine kinase inhibitor, has been approved for the treatment of advanced RCC. However, the impact of cabozantinib on the immune microenvironment of RCC remains poorly understood. Methods Kaplan-Meier survival curves were constructed to examine the correlation between intratumor infiltration of neutrophils and patient prognosis in RCC. Infiltration and effector function of neutrophils and T cells in response to cabozantinib treatment were investigated in a murine RCC model. Results A retrospective study of 307 RCC patients indicated that neutrophils were recruited into tumor tissues, and increased neutrophil infiltration was associated with improved clinical outcomes. In a murine model of RCC, cabozantinib treatment significantly increased both intratumor infiltration and anti-tumor function of neutrophils and T cells. Mechanistically, we found that cabozantinib treatment induced expression of neutrophil-related chemokines (CCL11 and CXCL12) and T cell-related chemokines (CCL8 and CX3CL1) in the tumor microenvironment. Furthermore, depletion of neutrophils and CD8 + T cells compromised the therapeutic efficacy of cabozantinib. Importantly, cabozantinib treatment induced long-term anti-tumor T cell response. Conclusions Our study revealed novel mechanisms of the therapeutic effects of cabozantinib on RCC by activating both neutrophil-mediated innate immunity and T cell-mediated adaptive immunity. These findings are of great significance for guiding the clinical use of cabozantinib and provide a good candidate for future combination therapy with T-cell therapies or other immunotherapies.