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

Abstract

It has been shown that γδ T cells protect against the formation of squamous cell carcinoma (SCC) in several models. However, the role of γδ 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 γδ T cells in a transgenic mouse model of carcinogenesis induced by HPV16 oncoproteins. Surprisingly, γδ T cells promoted the development of HPV16 oncoprotein-induced lesions. HPV16 oncoproteins induced a decrease in epidermal Skint1 expression and the associated antitumor Vγ5 γδ T cells, which were replaced by γδ T-cell subsets (mainly Vγ6 γδCCR2CCR6) 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 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 γδ T-cell subpopulations, thereby promoting angiogenesis and cancer development.

γδ T cells in cancer: a small population of lymphocytes with big implications

“…95 IL-17 + cd T-cell recruitment is supported by tumor chemokine secretion, such as CCL2/MCP-1, a molecular target for anticancer therapy and ligand for CCR2, which is highly expressed on tumor-infiltrating cd T cells. 99,100 Interestingly, in other models, recruitment of IL-17 + cd T cells to the subcutaneous B16 melanoma tumors and HPVinduced skin lesions, respectively, is associated with a downregulation of CCR6 expression, 91,96 indicating that the environmental setting in which the tumor develops might influence the phenotype of the immune cells recruited. 89,90 Indeed, CCR6 and its ligand CCL20 are associated with tumor progression in models of CRC and pancreatic cancer.…”

“…This is in line with the majority of reports on IL-17 production by other innate and adaptive immune cells, although the impact of IL-17 on tumor growth might depend on the type of cancer studied. 34,[88][89][90][91][92] In murine models of ovarian, pancreatic and lung cancers, IL-17-producing cd T cells in tumors were highly proliferative and displayed an activated phenotype. 34,[88][89][90][91][92] In murine models of ovarian, pancreatic and lung cancers, IL-17-producing cd T cells in tumors were highly proliferative and displayed an activated phenotype.…”

“…Interestingly, the IL-17 production in cd T cells via IL-1b axis is also described in promoting tumor metastasis in a spontaneous model of breast cancer metastasis. 89,91,[96][97][98] The chemokine receptor CCR6, involved in the trafficking of IL-17 + cells to tissues at steady state, is also expressed by IL-17 + cd T cells in the tumor bed of PDA and hepatocellular carcinoma. 95 IL-17 + cd T-cell recruitment is supported by tumor chemokine secretion, such as CCL2/MCP-1, a molecular target for anticancer therapy and ligand for CCR2, which is highly expressed on tumor-infiltrating cd T cells.…”

“…87 We and others have found that IL-17 + cd T cells are enriched not only in a variety of murine solid tumor models induced by implantation of tumorigenic cells, but also in spontaneous models of HPV-related carcinogenesis and breast cancer models, for which they are associated with metastasis. 34,[88][89][90][91][92] In murine models of ovarian, pancreatic and lung cancers, IL-17-producing cd T cells in tumors were highly proliferative and displayed an activated phenotype. 34,89,93 They induced angiogenesis and the recruitment of neutrophils, generally associated with poor prognosis in cancer.…”

IL ‐7‐dependent compositional changes within the γδ T cell pool in lymph nodes during ageing lead to an unbalanced anti‐tumour response

“…However, tumour‐promoting roles of the IL‐17‐producing γδ T‐cell subsets have emerged . Pro‐tumour mechanisms of IL‐17 produced by Vγ4 + and Vγ6 + γδ T cells include the promotion of angiogenesis and recruitment of immunosuppressive cells, such as myeloid‐derived suppressor cells (MDSCs) and peritoneal macrophages .…”