Neuro-immune modulation of pain in health and disease

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Project Summary: The majority of patients with advanced stage cancers experience moderate to severe pain, and more than half of all cancer patients report insufficient pain relief by the currently available therapeutics. Head and neck squamous cell carcinomas (HNSCC) involving the oral cavity and/or oropharynx are regarded as a particularly painful cancer type which produces coincident functional impairments that lead to difficulties in feeding, swallowing, and communication. These functional impairments substantially reduce quality of life for cancer patients and are associated with increased morbidity and mortality. Thus, there is a critical need for novel therapeutics that are capable of providing safe and effective pain relief. Moreover, any newly emerging pain therapeutic must be compatible with existing and emerging standard of care cancer treatments, such as cancer immunotherapy, which has emerged as the gold-standard treatment for many cancer subtypes over the last decade. We recently discovered that pain-sensing peripheral sensory neurons (nociceptors) express the innate immune regulator STING. Strikingly, activation of STING can produce antinociception in mice and non-human primates, both in steady-state conditions and in pathological pain states. This is noteworthy, as small molecule STING agonists have shown remarkable efficacy in promoting antitumor immunity and are currently being explored as cancer therapeutics in clinical trials. The objective of this proposal is to identify the cellular and molecular mechanisms by which STING regulates nociception, both in steady-state conditions and in HNSCC pain models. We hypothesize that STING dynamically regulates nociception in steady-state and disease conditions through a mechanism dependent on nociceptor-immune cell signaling and its subcellular localization. In Specific Aim 1, we will determine how STING signaling in peripheral sensory neurons, TRPV1+ nociceptors, and classical type-1 dendritic cells (cDC1s) each contribute to STING-mediated antinociception in health and disease, using syngeneic cancer pain models, conditional genetics, behavioral phenotyping, immune profiling, and biochemical and immunohistochemical approaches. In Specific Aim 2, we will determine how the subcellular localization of STING influences its molecular and physiological properties to influence nociception and antitumor immunity. Overall, completion of these experiments will substantiate STING as a unique “neuro-immunotherapy” target capable of conferring combinatorial analgesia and antitumor properties, a finding of immediate translational relevance given the paucity of options available to patients suffering from cancer pain.