Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 114, Issue 43, Pages E9056-E9065Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1712883114
Keywords
gamma delta T cells; viral oncogene; interleukin 17; functional heterogeneity; gammadelta
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Funding
- Fonds National de la Recherche Scientifique (F.R.S.-FNRS)
- Centre Anticancereux pres \'Universite de Liege
- Fonds Leon Fredericq (University of Liege)
- Fonds Van Buuren (Universite Libre de Bruxelles)
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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.
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