The Role of Dectin-1 Signaling in Altering Tumor Immune Microenvironment in the Context of Aging

Abstract

An increased accumulation of immune-dysfunction-associated CD4⁺Foxp3⁺ regulatory T cells (T_regs) is observed in aging oral mucosa during infection. Here we studied the function of T_regs during oral cancer development in aging mucosa. First, we found heightened proportions of T_regs and myeloid-derived suppressor cells (MDSC) accumulating in mouse and human oral squamous cell carcinoma (OSCC) tissues. Using the mouse 4-Nitroquinoline 1-oxide(4-NQO) oral carcinogenesis model, we found that tongues of aged mice displayed increased propensity for epithelial cell dysplasia, hyperplasia, and accelerated OSCC development, which coincided with significantly increased abundance of IL-1β, T_regs, and MDSC in tongues. Partial depletion of T_regs reduced tumor burden. Moreover, fungal abundance and dectin-1 signaling were elevated in aged mice suggesting a potential role for dectin-1 in modulating immune environment and tumor development. Confirming this tenet, dectin-1 deficient mice showed diminished IL-1β, reduced infiltration of T_regs and MDSC in the tongues, as well as slower progression and reduced severity of tumor burden. Taken together, these data identify an important role of dectin-1 signaling in establishing the intra-tumoral immunosuppressive milieu and promoting OSCC tumorigenesis in the context of aging.