Oncogenic HRAS-driven immune escape in cutaneous squamous cell carcinoma

Summary: Abstract Body: RAS mutations are recurrent in skin malignancies and HRAS mutations can be found in approximately 23% of cutaneous squamous cell carcinomas (cSCCs), the second most prevalent type of skin cancer. While RAS activity in various cancer hallmarks is well known, the role of oncogenic HRAS in creating a tumor-promoting microenvironment is less studied. Previous research indicates that oncogenic HRAS causes dose-dependent epidermal activation and inflammation. These mutations may shape the tumor microenvironment and contribute to immune evasion in cSCCs. To understand microenvironmental consequences of oncogenic HRAS signaling in skin, we introduced HRASQ61 and HRASG12V in healthy human keratinocytes and observed common and disparate effects of these activating mutations. The effects on immunity were contextual. On the one hand, both oncogenic variants induced a high pro-inflammatory response. On the other hand, they promoted expression of genes related to generation of immunosuppressive metabolites and their subsequent production. When investigating mice bearing HrasQ61- and HrasG12V-mutated skin tumors, we intriguingly observed differential immune infiltration pattern. While neutrophils are a major component of the immune infiltrate in both models, only the G12V-mutated tumors recruited macrophages, suggesting oncogenic variant-specific immune interactions. Importantly, we could disclose that oncogenic HRAS induces NETosis, contributing to further inflammation and immune evasion in the tumor microenvironment. Understanding the interplay between oncogenic HRAS signaling and immune escape provides insights into potential therapeutic strategies that can be translated into improved and personalized treatment, such as targeting NETosis to enhance anti-tumor immunity in mutated HRAS-driven cSCCs. Débora C. Radicchi^{1, 2}, Christine Gretzmeier², Dimitra Kiritsi², Alexander Nyström² 1. Biological Faculty, Albert-Ludwigs-Universitat Freiburg, Freiburg, Germany. 2. Dermatology, Universitatsklinikum Freiburg, Freiburg, Germany. Genetic Disease, Gene Regulation, Gene Therapy & Epigenetics