Contribution of cutaneous neuro-immune interactions to chemotherapy-induced peripheral neuropathy

While chemotherapy is the standard of care treatment for many cancer patients, a common side effect, chemotherapy-induced peripheral neuropathy (CIPN), is the leading cause of treatment discontinuation or dose reduction. This severe adverse event typically presents in the hands and feet as sensations of weakness, pain, burning, numbness, or tingling. Oxaliplatin is known to induce the highest incidence of neurotoxicity compared to other chemotherapies. Chronic oxaliplatin-induced peripheral neuropathy (OIPN) affects about 70% of oxaliplatin-treated patients, and its major symptoms last for months or years after treatment termination. Slow spontaneous recovery may occur in some patients, but lingering symptoms often result in permanent nerve damage. Little is known about mechanisms whereby oxaliplatin induces nerve damage, resulting in OIPN. The dorsal root ganglia (DRG) sensory nerve fibers extend to the periphery of the body and are known to interact with immune cells. Neuro-immune interactions are increasingly recognized in the pathobiology of CIPN, and several different types of immune cells have been implicated in the development of CIPN. However, CIPN studies have predominately investigated neuro-immune interactions at the DRG level; the peripheral neuro-immune interactions in the skin (specifically surrounding the hands and feet where CIPN most frequently presents) have been largely overlooked. To date, there is no comprehensive assessment of these skin neuro-immune interactions in the context of CIPN. Further, most current CIPN animal models test chemotherapeutic agents alone without cancer inoculation and effects of cancer on CIPN development are also overlooked. The objective of this proposed study is to bridge this research gap and characterize the neuro-immune interactions in the skin of tumor-bearing mice that have OIPN. Our specific aims are to (i) define how the cutaneous immune landscape is activated by tumor and repeated oxaliplatin and (ii) determine the mechanisms of cutaneous neuro-immune interactions mediated by tumor and repeated oxaliplatin. Using a tumor-bearing chronic OIPN mouse model, we will (i) define the cutaneous immune landscape using single cell RNA sequencing; (ii) determine how nerve and immune cells interact with one another in skin using immunohistochemistry; and (iii) explore the roles of cutaneous inflammation/immune cell component in OIPN development using proteomic analysis. Using an in vitro DRG culture system, we will address the effects of cancer-associated immune cells on the susceptibility of DRG neurons to oxaliplatin. This exploratory R21 proposal will (i) be the first to rigorously characterize cutaneous neuro-immune interactions in the tumor bearing and the chronic OIPN setting, (ii) provide robust data essential to establish a more specific hypothesis which lays the foundation for a future large-scale grant, and (iii) ultimately improve oxaliplatin-treated cancer patients’ quality of life.