Dense tumor innervation is associated with enhanced cancer progression and poor prognosis. We observed innervation in breast, prostate, pancreatic, lung, liver, ovarian, and colon cancers. Defining innervation in high-grade serous ovarian carcinoma (HGSOC) was a focus since sensory innervation was observed whereas the normal tissue contains predominantly sympathetic input. The origin, specific nerve type, and the mechanisms promoting innervation and driving nerve-cancer cell communications in ovarian cancer remain largely unknown. The technique of neuro-tracing enhances the study of tumor innervation by offering a means for identification and mapping of nerve sources that may directly and indirectly affect the tumor microenvironment. Here, we establish a murine model of HGSOC and utilize image-guided microinjections of retrograde neuro-tracer to label tumor-infiltrating peripheral neurons, mapping their source and circuitry. We show that regional sensory neurons innervate HGSOC tumors. Interestingly, the axons within the tumor trace back to local dorsal root ganglia as well as jugular–nodose ganglia. Further manipulations of these tumor projecting neurons may define the neuronal contributions in tumor growth, invasion, metastasis, and responses to therapeutics.

High-grade serous ovarian carcinoma (HGSC) is the most lethal gynecological malignancy, with poor survival rates attributable to both late diagnosis and resistance of tumors to standard-of-care chemotherapies. Recent therapeutic strategies aim to circumvent chemoresistance by targeting tumor-extrinsic factors that support the tumor microenvironment (TME). While TME-targeted therapies such as immunotherapy and anti-angiogenics have shown promise in other chemoresistant disease states, no substantial benefit has been observed in HGSC. We have recently observed that HGSC tumors are densely infiltrated by transient receptor potential vanilloid 1 (TRPV1+) sensory nerves that are otherwise absent in normal gynecological tissues. Tumor innervation has been shown to correlate with poor prognostic outcomes in other solid tumor types and thus warrants investigation in the context of HGSC. Our preliminary data using a syngeneic mouse model of HGSC shows that diphtheria toxin-mediated ablation of TRPV1+ nerves (Trpv1-DTA) attenuates HGSC tumor growth in vivo. Furthermore, preliminary immunohistochemical analysis of HGSC tumors from wild-type versus Trpv1-DTA mice has revealed differential infiltration of immune cell populations, indicating that tumor innervation may influence immunoreactivity within the TME. These results provide us with a basis for understanding how therapeutic targeting of tumor infiltrating nerve populations may sensitize HGSC tumors to immunotherapy. Citation Format: Hunter D. Reavis, Daniel W. Vermeer, Anthony C. Restaino, Allison Kruse, Matthew Knarr, Paola D. Vermeer, Ronny Drapkin. Infiltration of TRPV1+ nerves influences the ovarian cancer immune landscape [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr PR006.