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

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.

Grant Number: 5R01DE032018-04
NIH Institute/Center: NIH
Principal Investigator: Moran Amit