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Perineural invasion (PNI) and nerve density within the tumor microenvironment (TME) have long been associated with worse outcomes in head and neck squamous cell carcinoma (HNSCC). We investigate how nerves within the tumor microenvironment impact the adaptive immune system and tumor growth. RNA sequencing and proteomics data led us to identify cholinergic nerves as the potential drivers of tumor growth in human and mouse HNSCC. Using three syngeneic orthotopic murine models of HPV-unrelated HNSCC, experimental and pharmacologic manipulation of cholinergic output, and knockout mouse models, we discovered that activation of cholinergic nerves accelerate tumor growth by directly acting on the adaptive immune system. Cholinergic nerve release of calcitonin gene-related peptide (CGRP) directly inhibited CD8 T cell activity in vitro, and blocking cholinergic nerves pharmacologically or genetically increased CD8 T cell activity in vivo. These data support therapeutic translation of cholinergic nerve targeting of CGRP release to enhance antitumor immune response within the HNSCC TME. Citation Format: Laurel B. Darragh, Tiffany T. Pham, Michael M. Knitz, Alexander Nguyen, Laith A. Mukdad, Yazeed Alhiyari, Maie St. John, Sana D. Karam. Cholinergic nerve release of CGRP increases tumor growth in HNSCC by suppressing TILs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1834.

Surgical resection of advanced head and neck squamous cell carcinoma (HNSCC) poses a unique clinical challenge due to nearby vital structures necessary for speech, swallowing, and breathing. Aggressive surgical resection severely impairs functioning and quality of life. Despite considerable advancements in the treatment of HNSCC, long-term survival has continued to be poor in the past 30 years. The standard of care for most HNSCC remains surgery followed by adjuvant radiation and/or chemotherapy. To improve patient survival and preserve critical functions that directly impact quality of life, innovative treatment modality and delivery mechanisms have been explored, with promising results. Several novel drug delivery modalities offer a new potential for patients with advanced HNSCC. These thoughtfully engineered materials can exhibit release of chemotherapeutics at variable kinetics, provide enhanced imaging techniques allowing for minimization of radiation exposure, and optimize immunomodulatory signals to combat the tumor microenvironment.