Role of Neurokinin-1 Receptor Signalling in Immunomodulation of Tumor Development

Abstract

Neuro-immune communications play an important role in regulating various functions in homeostasis and diseases. Amongst different diseases, it plays a crucial role in modulating tumor development. Substance P (SP), a neuropeptide, is an integral part of the neuro-immune axis, and it plays a significant role in neuro-immune regulations. It promotes pro-inflammatory immune responses and affects many immune cells crucial for anti-tumor immunity. Although extensive work has been done on the effect of SP/neurokinin-1 receptor (NK1R) signaling in neurological and autoimmune disorders, very little is known about their effect on the immune cells in modulating the tumor microenvironment (TME) of different cancers. This study shows that SP-NK1R signaling decreases colorectal cancer (CRC) growth in a mouse model. Further profiling of the immune cell phenotypes using multidimensional spectral flow cytometry analysis revealed that SP specifically affects various CD8 T cell and CD4 T cell populations within the TME. SP promotes pro-inflammatory effector and memory CD8 T cells, Th17 cells, and Th1-like Th17 cells within the TME of CRC in mice. SP not only suppresses the proportions of Tregs within the tumor, but it also reduces the expression of immune-regulatory molecules like CTLA-4, GITR, and PD-1 on different CD8 T and CD4 T cells. Thus, we demonstrate that SP-NK1R signaling plays a crucial role in mounting anti-tumor immune responses against colorectal cancer. In addition, our finding gives a new dimension that suggests the functional relevance of incorporating the neuroimmune axis in designing therapeutic strategies to treat colon cancer.