UCSF

Although chronic inflammation promotes cancer development, an unresolved paradox is how tumors become proficient at evading the immune system. To achieve this, tumor oncogenes must both cooperate with inflammatory signals to promote tumorigenesis and drive immune evasion. In this study, we use gene expression networks to demonstrate the cooperative roles of two of the most frequently mutated oncogenes, Hras and Kras, in controlling inflammation during cutaneous squamous cell carcinoma (cSCC) development. First, we describe the role of Hras in orchestrating the tissue response to 12-O-tetradecanoylphorbol acetate (TPA), a tumor promoter used in the chemical carcinogenesis model of cSCC. In this model, Hras is necessary for TPA-induced promotion, as germline loss of Hras reduces tumorigenesis. We find that the TPA response induces recruitment of regulatory T cells in an Hras-dependent manner. We further demonstrate that the loss of Hras also leads to an increase in activated dendritic cells and neutrophils during the TPA response. These findings suggest that Hras may be necessary for neoplastic cells to survive TPA-induced inflammation. Second, we explored the role of Kras in evading anti-tumor immunity. In a pooled in vivo CRISPRi screen, we tested the hypothesis that genes strongly co-expressed with mutant Kras might mediate resistance to immune checkpoint blockade therapy with anti-PD1. From this screen, we identified 2 targets, Sgol2 and Rc3h2, which when knocked down successfully resensitized Kras mutant cSCCs to treatment with anti-PD1. Collectively, this supports the conclusion that Hras and Kras play fundamental, but distinct roles in adapting to inflammation at different stages of cSCC development.