Abstract P4-04-10: Pharmacological targeting of cholinergic receptors as a novel breast cancer immunotherapy

Abstract

Abstract There is a general consensus that the devastating effect of malignant breast cancers (MBCs) is due in part to the ability of breast tumors to exploit host immune functions by subverting normal mechanisms of immunosurveillance. For example, while immunotherapies based on immune checkpoint inhibition in lymphocytes have been associated with better prognosis in other cancers, the efficacy in breast cancer has been limited. We focus here on activating biochemical pathways in antigen-presenting dendritic cells (DCs) that are otherwise immunosuppressive to stimulate the activity of tumor-infiltrating lymphocytes through a novel mechanism. To this end, we recently discovered using an immune-competent mouse model of MBC that breast cancer cells exploit adaptive immune cells such as DCs that express CHRNA7, the α7 nicotinic acetylcholine receptor. Based on the importance of the CHRNA7 signaling pathway in the control of normal inflammation in macrophages in general, we show here that CHRNA7 stimulation in DCs leads to an activation of lymphocytes associated with a reduction in MBC. Specifically, mice lacking the CHRNA7 gene have (a) decreased survival, (b) increased tumor growth kinetics, (c) immunophenotyping revealed a reduction in the “cancer-permissive” phenotype in CHRNA7 KO mice, and (d), a commensurate reduction in T cell proliferation. Based on these mechanistic proof of principle studies, we demonstrate that in contrast to the loss of CHRNA7 in KO, pharmacological activation of CHRNA7 with AR-R17779 has the opposite effect by stimulating DCs to activate the adaptive immune response which leads to tumor progression and increased survival. These findings demonstrate the preclinical potential of AR-R17779 as a clinically relevant approach to stimulate the adaptive immune system through a novel pathway that has not been examined to date, and with a small molecule drug that is stable, specific and well-tolerated. Citation Format: Brian P. Eliceiri, Jin Qian, Sarah Blair. Pharmacological targeting of cholinergic receptors as a novel breast cancer immunotherapy [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-04-10.