Dynamic changes of exhaustion features in T cells during oral carcinogenesis

Abstract

Objectives: This study aimed to clarify the dynamic changes of exhaustion features in T cells during oral carcinogenesis.

Materials and methods: Mice were randomly divided into 4NQO group and control group. The exhaustion features of CD4⁺ and CD8⁺ T cells of both groups were detected by flow cytometry. Furthermore, multiplex immunohistochemistry was used to evaluate the expression of inhibitory receptors in human normal, dysplastic, and carcinogenesis tissues. Finally, anti-PD-1 antibody treatment was performed at the early premalignant phase of oral carcinogenesis.

Results: The proportion of naive T cells in 4NQO group was lower than those in control group, while the proportion of effector memory T cells was higher in 4NQO group. The expression of inhibitory receptors on CD4⁺ and CD8⁺ T cells increased gradually during carcinogenesis. In contrast, the secretion of cytokines by CD4⁺ and CD8⁺ T cells decreased gradually with the progression stage. Strikingly, those changes occurred before the onset of oral carcinogenesis. The expression of inhibitory receptors on T cells increased gradually as the human tissues progressed from normal, dysplasia to carcinoma. Interestingly, PD-1 blockade at the early premalignant phase could reverse carcinogenesis progression by restoring T cell function.

Conclusions: T-cell dysfunction was established at the early premalignant phase of oral carcinogenesis; PD-1 blockade at the early premalignant phase can effectively reverse T-cell exhaustion features and then prevent carcinogenesis progression.

Keywords: PD-1 blockade; T cell exhaustion; cytokine secretion; inhibitory receptors; oral carcinogenesis; regulatory T cell (Treg).