Toll-like receptor 3 signaling converts tumor-supporting myeloid cells to tumoricidal effectors

Abstract

Smoldering inflammation often increases the risk of progression for malignant tumors and simultaneously matures myeloid dendritic cells (mDCs) for cell-mediated immunity. PolyI:C, a dsRNA analog, is reported to induce inflammation and potent antitumor immune responses via the Toll-like receptor 3/Toll-IL-1 receptor domain-containing adaptor molecule 1 (TICAM-1) and melanoma differentiation-associated protein 5/IFN-β promoter stimulator 1 (IPS-1) pathways in mDCs to drive activation of natural killer cells and cytotoxic T lymphocytes. Here, we found that i.p. or s.c. injection of polyI:C to Lewis lung carcinoma tumor-implant mice resulted in tumor regression by converting tumor-supporting macrophages (Mfs) to tumor suppressors. F4/80− Mfs infiltrating the tumor respond to polyI:C to rapidly produce inflammatory cytokines and thereafter accelerate M1 polarization. TNF-α was increased within 1 h in both tumor and serum upon polyI:C injection into tumorbearing mice, followed by tumor hemorrhagic necrosis and growth suppression. These tumor responses were abolished in TNF-α −/− mice. Furthermore, F4/80 + Mfs in tumors extracted from polyI:Cinjected mice sustained Lewis lung carcinoma cytotoxic activity, and this activity was partly abrogated by anti-TNF-α Ab. Genes for supporting M1 polarization were subsequently up-regulated in the tumor-infiltrating Mfs. These responses were completely abrogated in TICAM-1 −/− mice, and unaffected in myeloid differentiation factor 88 −/− and IPS-1 −/− mice. Thus, the TICAM-1 pathway is not only important to mature mDCs for cross-priming and natural killer cell activation in the induction of tumor immunity, but also critically engaged in tumor suppression by converting tumor-supporting Mfs to those with tumoricidal properties.Toll-like receptor | tumor-associated macrophages | TRIF

PLD4 promotes M1 macrophages to perform antitumor effects in colon cancer cells

“…The detoxified derivative of LPS had also shown promise as an adjuvant of anticancer vaccines. A number of 79 clinical trials of this drug are ongoing (31). M1-type macrophages are capable of inducing lysis in various types of cancer cells, but the mechanism of action need further exploration.…”

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

“…In this study, we designed many nucleotide adjuvants and tested their functional properties. Our approach is timely since most dsRNA receptors have been identified in the mouse and human [1][2][3][4] , and their structures and properties have been known for a decade [32][33][34] . Based on our current understanding of the dsRNA response, poly(I:C) activates both TICAM-1 (ref.…”

PolyI:C–Induced, TLR3/RIP3-Dependent Necroptosis Backs Up Immune Effector–Mediated Tumor Elimination In Vivo

“…Tumors usually contain various types of macrophages concomitant with invasive properties (48). The recruited macrophages are obliged to support tumor progression, but often turn tumor suppressive in response to polyI:C via TNFa production (47). Like other myeloid species (48), ROS would be a macrophage-derived antitumor modulator induced via extracellular RNA stimulation.…”

“…However, the polyI:C/zVAD tumor regression was DC unrelated. Recently, polyI:C was found to act on tumor-associated macrophages to facilitate robust production of TNFa, resulting in hemorrhagic necrosis of tumors (47). Tumors usually contain various types of macrophages concomitant with invasive properties (48).…”