Tumor Promotion by Intratumoral Plasmacytoid Dendritic Cells Is Reversed by TLR7 Ligand Treatment

Abstract

Plasmacytoid dendritic cells (pDC) are key regulators of antiviral immunity. In previous studies, we reported that pDC-infiltrating human primary breast tumors represent an independent prognostic factor associated with poor outcome. To understand this negative impact of tumor-associated pDC (TApDC), we developed an orthotopic murine mammary tumor model that closely mimics the human pathology, including pDC and regulatory T cell (Treg) infiltration. We showed that TApDC are mostly immature and maintain their ability to internalize antigens in vivo and to activate CD4 þ T cells. Most importantly, TApDC were specifically altered for cytokine production in response to Toll-like receptor (TLR)-9 ligands in vitro while preserving unaltered response to TLR7 ligands (TLR7L). In vivo pDC depletion delayed tumor growth, showing that TApDC provide an immunesubversive environment, most likely through Treg activation, thus favoring tumor progression. However, in vivo intratumoral administration of TLR7L led to TApDC activation and displayed a potent curative effect. Depletion of pDC and type I IFN neutralization prevented TLR7L antitumoral effect. Our results establish a direct contribution of TApDC to primary breast tumor progression and rationalize the application of TLR7 ligands to restore TApDC activation in breast cancer. Cancer Res; 73(15); 4629-40. Ó2013 AACR.

Toll-like receptor-5 agonist, entolimod, suppresses metastasis and induces immunity by stimulating an NK-dendritic-CD8 + T-cell axis

“…The major clinical limitations of many TLR agonists are the risk of dose-limiting toxicities associated with their systemic delivery (10-12) and metastasis stimulation (13-15). Furthermore, some previously investigated TLR agonists are restricted to injection directly into tumor tissue (3,(16)(17)(18), an approach that will likely have limited therapeutic value in cancer patients with metastatic disease.TLR5 is unique among TLRs as a potential target for systemic anticancer immunotherapy. Studies have shown that the only known natural TLR5 agonist, flagellin, flagellin-expressing Salmonella bacteria, and a pharmacologically optimized flagellin derivative named entolimod (CBLB502) have antitumor effects in several tumor models (19-23), including mouse models of liver metastases (24-26).…”

“…The major clinical limitations of many TLR agonists are the risk of dose-limiting toxicities associated with their systemic delivery (10)(11)(12) and metastasis stimulation (13)(14)(15). Furthermore, some previously investigated TLR agonists are restricted to injection directly into tumor tissue (3,(16)(17)(18), an approach that will likely have limited therapeutic value in cancer patients with metastatic disease.…”

Toll like receptor 7 expressed by malignant cells promotes tumor progression and metastasis through the recruitment of myeloid derived suppressor cells

“…TLR7 stimulation has previously mostly reported to stimulate anticancer immunosurveillance, for instance through direct stimulation of TLRs on antigens presenting cells, leading to their maturation 39,40 . However, in recent years, TLR7 expression by tumor cells has been associated with a pro-tumoral effect in pancreatic adenocarcinoma 25 and in NSCLC 10,11 .…”

Biopathological Significance of TLR9 Expression in Cancer Cells and Tumor Microenvironment Across Invasive Breast Carcinomas Subtypes

“…It has been shown that pDCinfiltrating primary breast tumors represent an independent prognostic factor associated with poor outcome [55]. Investigating these subtypes of microenvironment cells will provide important clues in breast carcinogenesis and tumor progression.…”