Thomas D. Wang

Heightened Hif1a expression in tamoxifen-treated Sox2-GEMM

Hypoimmunogenic tumor microenvironment as SOX2+ OED transforms to HNSCC

Sox2-driven OED transformation potentiates the expansion of IL-1highSlc2a1highIFNlow myeloid cells

Most differentially expressed genes between the myeloid cells from normal mucosa and those from transformed epithelial tissues at the 2-week and 4-week time points

IL-1α primed MDSCs suppressed T cell proliferation

Top 200 most differentially expressed genes between EV-MOC2-E6/E7 and Sox2-expressing MOC2-E6/E7 cells

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.

Supplementary Table S1. Frag J-Jm Interactors

Supplementary Figure S2. Full-length GRAIL1 does not interact with DNAJA1-GFP.

Supplementary Figure S7. Design and testing of scrambled peptides as negative controls.