Dissecting Neuro-Immune Interactions in Cancer

PROJECT SUMMARY/ABSTRACT: Cancer is highly adept at exploiting normal physiological functions to support its growth. One important component of tissue physiology is neurons which weave through our organs, releasing neuropeptides into nearby tissue. Importantly, the role innervation plays in malignancy and

anti-tumor immunity remains largely unknown and understudied. Our preliminary analysis shows that tumor infiltrating immune cells express high levels of receptors for sensory neuropeptides, which further positively correlates with expression of genes associated with immune cell dysfunction. These data suggest that

innervation may play an important role in regulating anti-tumor immunity. To test this hypothesis, we propose strategies to investigate the role of innervation in cancer, and to determine how neuropeptide sensing on immune cells impacts anti-tumor immunity in the following objectives: Objectives of Unnerving Cancer: (1) Investigate the degree of sensory neuron innervation in cancer (2)

Determine how neuropeptide sensing on DCs impacts anti- tumor immune responses. Using reporter tools and multiplexed imaging, we will determine innervation of tumor tissues in pre-clinical models and patient samples. Building on our results, we will investigate the functional and transcriptional effects of neuropeptide sensing on immune populations using endogenous and syngeneic models.

Results from this project have the potential to significantly advance our current understanding of the nervous system's contribution to cancer. Therapeutically, exploiting the neuronal vulnerability of cancer using existing clinically approved neuromodulators has the potential to rapidly translate clinically for the prevention and

treatment of cancer. The legacy of this NCI funded interdisciplinary research will be to understand the neuro- immune communication in cancer, opening doors for novel therapeutic strategies. Keywords: Tumor Immunology, Immunotherapy, Cancer Neuroscience, Dendritic cells, Neuro-Immune Interactions Graphical Abstract: Tumor innervation correlates with poor survival in several tumours. I propose to study

neuronal density in Skin and Lung tumour, and query correlation of neuronal density to therapeutic responses. I hypothesise that Sensory Neurons release neuropeptides, including CGRP, which acts on receptor expressing dendritic cells (DCs). Together this leads to blunted DC responses perpetuating CD8+ T cell

dysfunction and tumor progression. Objective 1 Objective 2