Human papillomavirus oncoproteins induce a reorganization of epithelial-associated γδ T cells promoting tumor formation

Background: γδ T cells have been shown to protect against the formation of squamous cell carcinoma (SCC) in several models. Yet, the role of γδ T cells in human papillomavirus (HPV) associated uterine cervical SCC, the third cause of death by cancer in women, is unknown.
Method: We investigated the impact of γδ T cells in a transgenic mouse model of carcinogenesis induced by HPV16-oncoproteins. Human uterine cervical biopsies of women infected by HPV were also analyzed.
Results: Surprisingly, γδ T cells promoted the development of HPV16 oncoprotein-induced lesions. HPV16-oncoproteins induced a decrease in epidermal Skint1 expression and the associated anti-tumor Vγ5+ γδ T cells, which were replaced by γδ T cell subsets (mainly Vγ6+ γδlowCCR2+CCR6-) actively producing IL-17A. Consistent with a proangiogenic role, γδ T cells promoted the formation of blood vessels in the dermis underlying the HPV-induced lesions. In human cervical biopsies, IL-17A+ γδ T cells could be only observed at the cancer stage (SCC), where HPV-oncoproteins are highly expressed, supporting the clinical relevance of our observations in mice. Overall, our results suggest that HPV16-oncoproteins induce a reorganization of the local epithelial-associated γδ T cell subpopulations thereby promoting angiogenesis and cancer development.