Reprogramming tumor microenvironment in cancer immunotherapy (P4274)

Abstract

Abstract Type-1 immune effector cells (CTLs, Th1 and NK cells) express high levels of CXCR3 and CCR5 and depend on the relevant chemokine ligands (CXCL9, CXCL10 and CCL5) for entry into tumor microenvironments. We observed that local production of prostaglandin (PG)E2 suppresses the induction of immune effector cell and selectively inhibits the production of the effector cell-attracting chemokines within peritoneal tumors (ovarian and colorectal cancers and different forms of peritoneal carcinomatosis). COX2 is also the key factor driving the MDC/CCL22- and SDF1/CXCL12-mediated accumulation of Tregs and myeloid-derived suppressor cells (MDSCs) in tumor tissues, orchestrating local inhibition of CTL function. COX2 blockers antagonized the accumulation and suppressive function of MDSCs and proved to be a necessary (but not sufficient) element of strategies aimed at restoring local immunosurveillance. While TLR-ligands used as stand-alone vaccine adjuvants can amplify the PGE2-driven suppressive events, their combination with COX2 inhibitors and IFNα allows to selectively induce effector cell-attracting chemokines within tumors (bu tnot marginal tissues) and suppress the MDSC- and Treg-attracting chemokines (CXCL12 and CCL22). Our current trials evaluate the effectiveness of tumor-selective conditioning of tumor microenvironments to promote the entry of spontaneously-arising and vaccination-induced CTLs into tumors and counteracting local immunosuppression.