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

It has been shown that gamma delta T cells protect against the formation of squamous cell carcinoma (SCC) in several models. However, the role of gamma delta T cells in human papillomavirus (HPV)-associated uterine cervical SCC, the third-leading cause of death by cancer in women, is unknown. Here, we investigated the impact of gamma delta T cells in a transgenic mouse model of carcinogenesis induced by HPV16 oncoproteins. Surprisingly,gamma delta T cells promoted the development of HPV16 oncoprotein-induced lesions. HPV16 oncoproteins induced a decrease in epidermal Skint1 expression and the associated antitumor V gamma 5(+) gamma delta T cells, which were replaced by gamma delta T-cell subsets (mainly V gamma 6(+) gamma delta(low)CCR2(+)CCR6(-)) actively producing IL-17A. Consistent with a proangiogenic role, gamma delta T cells promoted the formation of blood vessels in the dermis underlying the HPV-induced lesions. In human cervical biopsies, IL-17A(+) gamma delta T cells could only be 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 gamma delta T-cell subpopulations, thereby promoting angiogenesis and cancer development.