Early changes in the immune microenvironment during oral tumorigenesis reveal an unexpected protective role of M2 macrophages in oral potentially malignant disorders

Understanding the dynamics of the immune microenvironment is critical to the development of immuno-prevention strategies for the prevention of oral potentially malignant disorders transformation to oral squamous cell carcinoma (OSCC). We generated gene expression profiles of the microdissected epithelial and stromal compartments normal mucosa, hyperplasia, dysplasia and invasive tumors in the 4-nitroquinolein (4-NQO) murine model of oral carcinogenesis. Most gene expression changes were observed in the stromal compartment and related to immune biological processes. Immune cell deconvolution identified infiltration by the macrophage population as the most important quantitatively especially at the stage of dysplasia. In 86 patients with oral leukoplakia, three M2 macrophages signatures were independently associated and highly predictive of improved oral cancer-free survival. Overall design: We generated gene expression profiles of the microdissected epithelial and stromal compartments normal mucosa, hyperplasia, dysplasia and invasive tumors in the 4-nitroquinolein (4-NQO) murine model of oral carcinogenesis. Genes differentially expressed at each step of transformation were defined. Immune cell deconvolution and enrichment scores various biological processes including immune-related ones were computed. Immunohistochemistry was performed to characterize the immune infiltrates by T-cells (T-cells CD3+, helper CD4+, cytotoxic CD8+, regulatory FoxP3+), B-cells (B220+) and macrophages (macrophages F4/80+, M1 iNOS+, M2 CD163+) at each histological step. Enrichment of three independent M2 macrophages signatures were computed in 86 oral leukoplakia with available clinical outcome.