PD-1 and IL-10: partners in crime against anti-tumor immunity in ovarian cancer. (TUM9P.1011)

Abstract

Abstract PD-1: PD-L1 is a major inhibitory axis that acts to suppress tumor-rejecting effector responses. In addition to its expression and inhibitory functions in T and B cells; PD-1 has also been shown to be expressed on and thereby impact the functions of cells of innate arm such as dendritic cells (DCs) primarily at the tumor site but not in the periphery. We show here that one of the culprits in the tumor microenvironment responsible for enhancing PD-1 expression on the tumor-associated DCs is the cytokine IL-10; which is expressed in abundance in many malignancies including ovarian cancer. Based on inhibition and knockdown studies, we show that IL-10 mediated PD-1 expression depends on STAT3 activation. Using murine model of ovarian carcinoma (ID8), we show that tumor-associated DCs express not only high levels of PD-1 on the surface but also have increased expression of STAT-3 and p-STAT3 compared to splenic DCs. Blockade of PD-1 on DCs led to increased production of IL-10 which correlated with a further increase in PD-1 expression. In in vivo studies, blockade of PD-1 and IL-10 neutralization as combination therapy augmented the anti-tumor response in ID8 ovarian tumor bearing mice; leading to a decrease in tumor mass and a significant increase in survival. These results show that IL-10 and PD-1 pathway intersect in DCs in theTME hence making them attractive targets for therapy of ovarian cancer.