Genetic and pharmacological targeting of nicotinic acetylcholine receptor action blocks tumor progression in mouse models of breast cancer.

Abstract

Effective small molecule therapies are a major unmet need in triple-negative breast cancer. Therefore, we examined the mechanism of action of a novel cancer therapeutic target in preclinical mouse models focusing on the α7 nicotinic acetylcholine receptor (CHRNA7). E0771 breast tumor cells were implanted into CHRNA7KO mice to determine the role of CHRNA7, which is expressed in tumor-associated myeloid immune cells. We observed that tumor-bearing CHRNA7KO mice had decreased survival and increased tumor burden linked to a CHRNA7-mediated reduction in immune cell activation. Based on the tumor permissive phenotype of CHRNA7KO mice, we tested the effect of a small molecule agonist of CHRNA7, AR-R17779, in several mouse models of breast cancer. For example, in both the E0771 tumor model and PyMT tumor models, treatment with AR-R17779 increased survival. In the 4T1 breast tumor model, treatment with AR-R17779 also increased survival, with a well-defined reduction in primary tumor burden and lung metastases. The antitumorigenic effects of AR-R17779 were linked to an adaptive immune response based on in vivo studies showing a survival benefit when AR-R17779 was administered as a combination therapy with anti-PD-L1, demonstrating that the effects of AR-R17779 were dependent on CD8 T cells, and in vitro studies showing AR-R17779 treatment of dendritic cells increased T cell activation. Together these findings supported the importance of CHRNA7 as a novel therapeutic target expressed on dendritic cells based on its role in potentiating the adaptive immune response in mouse models of breast cancer.