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.