Traditional cancer therapy involves surgery, radiotherapy, and chemotherapy. These modalities aim to ablate the tumor, yet generally the disease relapses due to the inefficiencies of the therapy and the ensuing growth of distant and/or resistant micrometastases. Immunotherapy is a new paradigm referring to the reactivation of the immune system by monoclonal antibodies against inhibitory molecules that are expressed on immune cells in the tumor microenvironment (TME). Monoclonal antibodies against CTLA-4, PD-1, and PD-L1 have been approved for clinical use in multiple cancers and can induce long-term, durable immune responses that result in the clearance of tumors. The most important advantage of immunotherapy is that, thanks to the evolving nature of the immune system, a responding patient is often cured of cancer.

This is the first therapy to accomplish such persistent results. Its biggest downside, however, is that a large group of patients do not respond. This observation led to the hypothesis that there are additional inhibitory mechanisms in the tumor and that these need to be addressed to improve the benefit of immunotherapy.

In this study, we propose to modulate neurotransmitters (NT) to enhance the response to immunotherapy. In preliminary data, we show that NTs exist in tumors, and the immune cells have the ability to detect them. It has also been shown in other studies, including our previous work, that NTs suppress immune function. Therefore, connecting these two together, we propose that NTs in tumor suppress immune cells. As a result, we propose that disrupting the production of NTs in the TME and disrupting their sensing by the immune cells can both increase the response to immunotherapy. There are already many FDA-approved drugs to modulate these pathways, therefore any results we find are highly likely to impact clinical care and do so rapidly.