Modulating tumor growth by triggering TLR4 on tumor cells

MARIANA MACCIONI

Buenos Aires

Simposio; First Franco-Argentine Immunology Congress: FAIC 2010; 2010

SociedadArgentina de Inmunologia

Toll like receptors (TLRs) are key sensor of microbes and are expressed on sentinel cells of the immune system.  TLRs agonists are potent activators of innate immune responses, activating antigen presenting cells and promoting adaptive immune response.  Their use as adjuvants to reinforce the immune response against tumors is among the first and oldest strategies used in anticancer immunity, even before these receptors were described.  Recently, functional TLRs have been shown to be expressed in numerous cancer cells, but their significance has only recently begun to be explored.  Our lab is interested in understanding the possible role that TLR4 could be playing in a sterile environment, like tumors. We have reported the consequences of activating TLR4, the receptor for bacterial lipopolisaccharide in tumor cells in different animal models of cancer.  We have observed that the activation of TLR4 in tumor cell lines in vitro inhibits the consequent tumor outgrowth in vivo and that this effect is not due to a change on the proliferation/apoptosis balance of the tumor cells. This in vivo inhibition of tumor growth depends exclusively on TLR4 present on tumor cell themselves and not on antigen presenting cells from the host, using host mice deficient for TLR4 (TLR4 lps-del). Preliminary data indicates that the T cell compartment is somehow involved in the described phenomenon since the inhibitory effect observed is not seen in athymic nude mice and the phenotype and function of tumor infiltrating lymphocytes purified from tumors induced by TLR4-activated cells is also modified.   We hypothesize that TLR4 signaling in tumor cells in vitro induces the expression of proinflammatory mediators, which could dramatically alter the maturation state of dendritic cells present at the site of inoculation, switching the type of immune response elicited against the tumor. Our goal is to understand the cellular and molecular mechanisms involved in this phenomenom with the idea of opening up new avenues for understanding the role of TLR4 on tumor cells and for identifying potential new therapy strategies for cancer.