IL-1α Expands SLC2A1highSPP1highIFNlow Myeloid Cells to Drive Immune Escape and Malignant Transformation of Precancers

Abstract Head and neck squamous cell carcinomas (HNSCC) are preceded by potentially malignant precursor lesions, highlighting the need for strategies to discern which precancerous lesions harbor a high risk for malignant transformation. In this study, we developed a unique genetically engineered mouse model by inducing oral epithelial cell–specific amplification of Sox2, which recapitulates the malignant transformation of epithelial dysplasia to HNSCC with high histologic and phenotypic resemblance to human tumors. SOX2 promoted the release of IL-1α and CCL2, expanding inflammatory monocytes. The recruited myeloid cells exhibited a distinct, early, high-risk signature of high levels of IL-1α, solute carrier family 2 member 1 (SLC2A1), secreted phosphoprotein 1 (SPP1), and low levels of type I interferon (IFN-I) targets, and intralesional SLC2A1high myeloid cells were more suppressive than their SLC2A1low counterparts. Brief priming of myeloid cells with IL-1α desensitized them to stimulator of IFN genes (STING) agonists and enhanced the suppressive effects of myeloid-derived suppressor cells on T-cell activation. Mechanistically, IL-1 activation repressed the expression of DHHC3/7 enzymes that palmitoylate STING. Early blockade of IL-1 signaling using pharmacologic and genetic approaches similarly reduced the most suppressive subsets of myeloid cells, promoted immune surveillance against the progression of epithelial dysplasia, and extended survival. This work establishes a central high-risk myeloid cell transcriptomic program, characterized by elevated levels of IL-1α, SLC2A1, and SPP1, that leads to irreversible immune escape upon transformation of precancerous epithelial lesions. Significance: SLC2A1highSPP1highIFNlow myeloid cells are a central feature of high-risk epithelial premalignancy that are induced by SOX2 activity in epithelial cells and can be inhibited by targeting IL-1 signaling to inhibit tumorigenesis.