Crucial immunological roles of the invasion front in innate and adaptive immunity in cervical cancer.

BACKGROUND: The immunostimulatory actions of innate and adaptive immune responses play a crucial role in the cancer-immunity cycle. Although cervical cancer (CC) exhibits a high recurrence rate, the relation with lymphocytes in the tumor tissue have not been analyzed. METHODS: We analyzed NKT, NK, and T cells, not only in peripheral blood (PB), but also tumor tissue through histological analysis from 23 patients with CC collected before treatment. A correlation of them between PB and the tumor tissue were assessed. RESULTS: We detected functional NKT and NKG2D(hi) NK cells and effector CD4(+) Tregs in PB. In the tumor, we detected the infiltration of LAG-3(+) TIM-3(+) CD4(+) and CD8(+) T cells rather than NK cells particularly in the invasion front (IF) by fluorescent multiplex immunohistochemistry. The heatmap and correlation analysis revealed that LAG-3(+) TIM-3(+) CD8(+) T cells are highly associated with CD69(+) CD103(-) exhausted CD8(+) T cells. We identified the statistical relationship between CD4(+)Tregs in PB and the number of LAG-3(+) TIM-3(+) CD4(+) T cells in the IF, which may be related to recurrence in patients with CC. CONCLUSIONS: LAG-3(+) TIM-3(+) T cells located in the IF may play a key role in regulation of the tumor immune microenvironment.