Dolly Jain, Nishant Pandey, Somesh K Jha, Shreya Sinha, Ragini Singh, Junaid Alam, Bharti Aggarwal, Neelam Chauhan, Arunima Acharya, Anu P V, Vandana Dhangar, Ritika Bhargava, Nikhil K Chourasiya, Ali Khan, Arnab K Sahoo, Debasish Nath, Lalita Mehra, Kajal Rana, Poonam Yadav, Jahanvi Ralhan, Saroj Rajput, Asish Pal, Arindam Maitra, Santiswarup Singha, Rajesh Panwar, Satish Khurana, Ujjaini Dasgupta, Sandeep K Bhoriwal, Jyothi S Prabhu, Prasenjit Das, Veena S Patil, Avinash Bajaj
We report presence of cholinergic nerve fibers in the periphery and stroma of colon cancer tissues and their correlation with poor T cell and increased macrophage infiltration. We employed hydrogel-mediated localized delivery of an FDA-approved local anesthetic, bupivacaine (BUP), to target acetylcholine (ACh)-mediated crosstalk of cholinergic neurons with cancer and immune cells. Localized BUP-Gel therapy promotes T cell-mediated tumor inhibition and enhances the antitumor response of systemic chemotherapy and immunotherapy. Further, blockade of cancer- and immune cell-specific ACh receptors inhibits tumor growth, alters the TME, and augments the impact of chemotherapy and immunotherapy. Finally, we demonstrate that ACh receptor antagonists polarize macrophages toward an M1-like phenotype and activate T cell immunity in tumor explants of patients. Therefore, targeting cholinergic signals through localized delivery of anesthetics, as well as direct immune reprogramming via cholinergic receptor antagonists, may provide a means to modulate this tripartite crosstalk, with potential implications for therapeutic strategies.