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

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. Here, we developed a unique genetically engineered mouse model (GEMM) 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, SLC2A1, 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 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.