COX-2 inhibitor prevents tumor induced down regulation of classical DC lineage specific transcription factor Zbtb46 resulting in immunocompetent DC and decreased tumor burden

Abstract

The interaction between the immune and tumor cells in the microenvironment is an important factor deciding the progression of cancer. Though many of the soluble mediators in the microenvironment that mediate immunosuppression are known, the mechanism by which the tumor affects the distal progenitors is not known. We report that the tumor derived prostanoids down regulated classical dendritic cells DC (cDC) lineage specific transcription factor Zbtb46 in the progenitor cells which affects its differentiation. Prostanoids also induced ERK/CREB/IL-10 signaling pathway in DC that is more important for maturation of DC. This was observed under in vitro as well as in vivo conditions leading to phenotypic and functional impairment of DC. siRNA mediated knockdown of Zbtb46 and not exogenous IL-10 mimicked the effects of tumor conditioned medium (TCM) on suppression of maturation markers. Treatment of tumor cells with COX-2 inhibitor NS-398 averted TCM induced phenotypic impairment of DC in vitro. Treatment of tumor bearing mice with NS-398 prevented tumor induced down regulation of Zbtb46 resulting in immunocompetent DC which in turn led to a decrease in tumor burden. The effects of NS-398 was indeed through immunomodulation was corroborated by no such response in SCID mice. Our study provides novel insight into the distal regulation of progenitor cells by tumor and the importance of Zbtb46 expression in anti-tumor immunity. These results identify Zbtb46 expression as an indicator of immunocompetent DC in tumor and also highlights that COX-2 inhibitors could be useful in cancer immunotherapy.