Harnessing the nervous system to overcome resistance to immunotherapy in oral cancer

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PROJECT SUMMARY/ABSTRACT To maximize their growth and metastatic potential, solid tumors promote the formation of new nerve fibers in the tumor microenvironment (TME). In patients with oral, prostate, breast, gastric, pancreatic, and other cancers, high densities of nerve fibers in the TME are associated with poor clinical outcomes. We proved that oral cancer cells induce a unique heterogeneous composition of tumor-associated neurons (TANs) in the TME. The nervous system plays important roles in homeostasis and inflammatory responses in tissues. However, the regulation of immune cells by nerves remains largely unclear. Our long-term goal is to elucidate the reciprocal nerve-cancer signals that drive cancer progression to identify novel targets for therapy and for overcoming immunotherapy resistance. Our preliminary data show that neurons communicate with immune cells directly through the expression of immunomodulatory molecules and indirectly through paracrine, adrenergic-dependent cancer cell signaling. The overall hypothesis that we will test in the proposed project is that TANs induce a maladaptive immune response that supports tumor progression. These newly formed, reprogrammed TANs regulate the immune response through a multistep mechanism that includes the transformation of quiescent neurons into sprouting cells that can infiltrate and interact with other cell types, release adrenergic neuroactive molecules, and support the development of an immunosuppressive microenvironment. Each of these steps may promote tumor progression and therapy resistance. The proposed research is innovative because it will capitalize on new concepts in immunology and cancer biology using advanced model systems to yield insights into the mechanisms of tumor progression and identify new targets for cancer therapy based on neuro-immune crosstalk. This cross-disciplinary proposal will combine expertise from oncology, immunology, cell biology, neurobiology, cancer genetics, pathology, and biostatistics in two specific aims across the two labs (Amit and Calin). Aim 1: Determine the mechanisms by which neuron-dependent cancer cell signaling regulates cytotoxic T-cell function. We will use pharmacological and genetic approaches combined with advanced spatial imaging techniques (for both protein and RNA) in syngeneic mouse models to understand how reprogrammed neurons regulate cytotoxic T-cell antitumor activity. Deciphering how TANs exert both antitumor immune activation and suppression activity through adrenergic signaling and immune checkpoint expression respectively, will allow us to leverage safe, affordable and well established neuromodulatory approaches to overcome immunosuppression in cancer. Aim 2: Identify the extracellular vesicle-shuttled driver miRNAs of TAN reprogramming and their roles in oral cancer progression. Using human-derived sensory neurons and functional genomic approaches, we will investigate the miRNA-dependent functional plasticity of immunomodulatory genes in TANs. The completion of the proposed studies will pave the way for treatment strategies that target the neuronal mechanisms associated with immunosuppression and reverse resistance to immunotherapy. Therapeutic approaches targeting this critical component of tumor biology are anticipated to improve patients' survival, treatment responses, and quality of life.