A complement atlas of head and neck squamous cell carcinomas to reveal intratumoral complement control and identify factor H as a therapeutic target in oral cavity and HPV-negative oropharyngeal tumors.

Abstract

e18049 Background: Oral Cavity Squamous Cell Carcinoma (OCSCC) and HPV-negative oropharyngeal SCC (HPV-negative OPSCC) together account for nearly 40% of Head and Neck SCC (HNSCC) and remain an unmet clinical need, with poor prognosis and limited benefit from multimodal therapies, including immune checkpoint inhibitors. The innate immune complement system has emerged as a druggable pathway in cancer, with strategies targeting C3a/C5a signaling or tumor-bound complement regulators to restore membrane attack complex (MAC)–mediated cytotoxicity. GT103, an antibody targeting tumor cell–associated complement regulator Factor H (FH), exemplifies this approach and is currently being evaluated in lung cancer in combination with anti-PD1. However, the role and regulation of complement activation across HNSCC subtypes remain poorly defined. Methods: We established a comprehensive complement atlas of HNSCC using an integrated Complementomics approach combining hyperplex imaging, plasma profiling, and clinical annotation from an institutional longitudinal biobanking cohort: SCANDARE (NCT03017573). Results: We enrolled 159 patients with early-stage HNSCC in the SCANDARE study. Plasma profiling of 17 complement proteins and activation fragments revealed selective alternative pathway activation in OCSCC and OPSCC, with coordinated elevation of Ba and the anaphylatoxins C3a, and C5a. Tumor profiling revealed a dense infiltration of C5aR1-positive macrophage and neutrophil subsets, driven in part by local C5a generation in OCSCC and OPSCC. In situ complement cascade did not reach the terminal step with formation of cytotoxic Membrane Attack Complex (MAC). This could be explained by the binding of FH to tumor cells surface of OCSCC and OPSCC HPV-negative, but not OPSCC HPV-positive. This FH was likely derived from the circulation, as local expression was minimal and it was elutable from our ex vivo preclinical model (Patient Tumor-Derived Fragment), indicating active local inhibition of alternative pathway–mediated cytotoxicity. As autoantibodies against this form of tumor-bound FH tumor neoantigen were protective in lung and renal cancer, we searched them in HNSCC. Positivity was observed in only a small number of patients, primarily in FH-rich OCSCC and HPV-negative OPSCC, suggesting that this potentially protective autoimmunity is rare. Conclusions: OCSCC and OPSCC HPV-negative exhibit a distinctive complement phenotype characterized by systemic anaphylatoxin generation without intratumoral complement-mediated cytotoxicity, mediated by tumor cell-associated FH. Targeting this FH with GT103 may overcome the regulatory barrier, restore immunogenic cell death mediated by the MAC, and enhance responses to immunotherapy, supporting clinical evaluation in these HNSCC subtypes.