γδ17T Cells Aggravate Carcinogen-Induced Oral Squamous Cell Carcinoma

Abstract

Oral squamous cell carcinoma (OSCC) is a highly aggressive malignancy, with a low 5-y survival rate and frequent local recurrence or metastasis. This study explores the role of γδT cells in the development and progression of OSCC. γδT cells, which exhibit innate and adaptive immune characteristics, are known for their dual role in cancer, acting as anti- and protumor agents depending on the context. Using a murine model of OSCC induced by the carcinogen 4-nitroquinoline-1-oxide (4NQO), which adequately mimics the progression of human OSCC, we investigated the impact of γδT cells on tumor growth and the tumor microenvironment. We first characterized the γδT cells of the tongue epithelium, the primary site for cancer development in this model. The results indicate that γδT cells are predominantly of the Vγ6+ subset, expanding postnatally in a microbiota-dependent manner. Upon 4NQO administration, depletion of γδT cells did not significantly alter the kinetics of OSCC progression but did result in a reduction in tumor size and number, suggesting a role in promoting tumor growth. Interestingly, the absence of IL-17, a key cytokine produced by the Vγ6+ subset, also resulted in reduced tumor volume without affecting disease progression, corroborating the protumor role of these cells in OSCC. Further analysis revealed that IL-17–producing γδT cells facilitate angiogenesis within the tumor microenvironment by promoting the expression of angiogenic factors. Of note, while 4NQO treatment increased the oral microbial load and altered its composition, IL-17 deficiency did not affect the oral microbiota, indicating that the effects of IL-17–producing γδT cells on OSCC are independent of microbial changes. This study highlights the pathologic role of IL-17–producing γδT cells in OSCC, particularly in promoting tumor growth through angiogenesis. This underscores the importance of γδT cells in OSCC and the need for further research into therapeutic strategies targeting these cells.