EP012/#891 Expression of chemokine receptor and suppression of inhibitory receptors of CD8 T cell eradicated effectively cervicovaginal tumor in mouse

Objectives

Activation of exhausted CD8 T cell and migration of immune cells into tumor site is an important for overcoming resistance to cancer therapy. We evaluated the role of suppression of inhibitory receptors and chemokine axis in cervicovaginal tumor bearing mouse.

Methods

C57BL/6 mice were categorized into four groups according to treatment modality. Mice were challenged with 1×10⁵ TC-1 cells on cervix and vagina. HPV DNA therapeutic vaccine was injected intramuscularly and intratumoral injection of GMCSF was performed. The mice were harvested on day 21 and immune cells were investigated by flow cytometry. We checked the expression of inhibitory receptors of CD8 T cells, including PD1, TIM3 and LAG3. Chemokine axis such as CXCL9, CXCL10, and CXCR3 were evaluated to know migration mechanism.

Results

Combination of HPV DNA vaccine and GMCSF resulted in significantly lower expression of TIM3 inhibitory receptors of CD8+ T cells in tumor (p<0.05). However, expression level of PD1 and LAG3 was not changed after combination therapy. They significantly induced accumulation of tumor specific CD8 T cell in tumor site and increased expression of CXCR3 on tumor infiltration CD8 T cell (p<0.05). CXCL9, chemokine, was overexpressed in cervicovaginal tumor after combination therapy (p<0.05). However, expression level of CXCL10 was not changed after combination therapy. Finally, mice treated with combination therapy survived significantly longer than other groups with single therapy (p<0.05).

Conclusions

In conclusion, we overcame T cell exhaustion and identified chemokine axis during migration of CD8 T cell into cervicovaginal tumor using HPV DNA vaccine and GMCSF.