Opposing Effects of Toll-like Receptor (TLR3) Signaling in Tumors Can Be Therapeutically Uncoupled to Optimize the Anticancer Efficacy of TLR3 Ligands

Abstract

Many cancer cells express Toll-like receptors (TLR) that offer possible therapeutic targets. Polyadenylicpolyuridylic acid [poly(A:U)] is an agonist of the Toll-like receptor TLR3 that displays anticancer properties. In this study, we illustrate how the immunostimulatory and immunosuppressive effects of this agent can be uncoupled to therapeutic advantage. We took advantage of two TLR3-expressing tumor models that produced large amounts of CCL5 (a CCR5 ligand) and CXCL10 (a CXCR3 ligand) in response to type I IFN and poly(A:U), both in vitro and in vivo. Conventional chemotherapy or in vivo injection of poly(A:U), alone or in combination, failed to reduce tumor growth unless an immunochemotherapeutic regimen of vaccination against tumor antigens was included. CCL5 blockade improved the efficacy of immunochemotherapy, whereas CXCR3 blockade abolished its beneficial effects. These findings show how poly(A:U) can elicit production of a range of chemokines by tumor cells that reinforce immunostimulatory or immunosuppressive effects. Optimizing the anticancer effects of TLR3 agonists may require manipulating these chemokines or their receptors. Cancer Res; 70(2); 490-500. ©2010 AACR.

Tumor-Infiltrating Monocytic Myeloid-Derived Suppressor Cells Mediate CCR5-Dependent Recruitment of Regulatory T Cells Favoring Tumor Growth

“…Furthermore, in a mouse model of pancreatic adenocarcinoma, knockdown of CCL5 production in tumors resulted in the delayed tumor growth (20). In addition, CCL5/ CCR5 blockade improved the efficiency of immunochemotherapy (48). In our models, tumor-infiltrating CD8 + T cells expressed CCR5 but their accumulation in tumors in CCR5-deficient mice was higher compared with wt mice, indicating that CCR5 expression was not required for their tumor infiltration.…”

Defined TLR3-specific adjuvant that induces NK and CTL activation without significant cytokine production in vivo

“…cM362-140 activated TICAM-1 for DC maturation, but barely induced chemokine production or necroptosis in tumour cells ( Supplementary Fig. 10), which were reported as a direct action of poly(I:C) 29,30 . Therefore, cM362-140 eliminates major inflammatory responses caused by poly(I:C).…”

Gut microbiome and anticancer immune response: really hot Sh*t!

“…Second, cellintrinsic effects such as direct activation of antigen-presenting cells located in tumor beds by bacterial cell walls or microbial components could reset myeloid cell functions or reprogram Treg bearing TLRs and/or parenchymal cells that respond to TLRs by chemokine or inflammatory cytokine release or apoptosis. 82 Third, the differentiation of anticommensal T cells could provide helper cytokines or costimulatory factors for anticancer T cells to be driven. The role of IL-2/IL-15, type 1 or type 2 IFNs or CD40/CD40L interactions could be explored among other candidates.…”