Administration of 6-gingerol greatly enhances the number of tumor-infiltrating lymphocytes in tumors

Tumor-infiltrating lymphocytes (TILs) play critical roles in host anti-tumor immune responses. It is known that cancer patients with tumor-reactive lymphocyte infiltration in their tumors have better prognoses, while patients with tumors infiltrated by immunosuppressive cells have worse prognoses. We found that administration of 6-gingerol, which is a component of ginger, inhibited tumor growth in several types of murine tumors, such as B16F1 melanomas, Renca renal cell carcinomas and CT26 colon carcinomas, established by inoculating tumor cells on the flanks of mice, although it did not lead to complete eradication of the tumors. 6-gingerol treatment of tumor-bearing mice caused massive infiltration of CD4 and CD8 T-cells and B220⁺ B-cells, but reduced the number of CD4⁺Foxp3⁺ regulatory T-cells. The CD8 tumor-infiltrating T lymphocytes in 6-gingerol-treated mice strongly expressed IFN-γ, a marker of activation of CTL CD107a cells, and chemokine receptors that are expressed on T_H1 cells, such as CXCR3 and CCR5. To test whether 6-gingerol could promote infiltration of tumor antigen-specific CD8 T-cells into tumors, we adoptively transferred CFSE-labeled OT-1 CD8 T-cells into EG7 tumor-bearing mice. We found that CD8 T cells isolated from 6-gingerol pre-treated OT-1 mice, but not from control OT-1 mice, infiltrated massively into tumors and tumor draining lymph nodes and divided several times. Our results strongly suggest that 6-gingerol can be used in tumor immunotherapy to increase the number of TILs.