IFNb PRODUCED BY TLR4-ACTIVATED TUMOR CELLS IS INVOLVED IN IMPROVING THE ANTITUMORAL IMMUNE RESPONSE

NICOLÁS NÚÑEZ, VIRGINIA ANDREANI, MARÍA INÉS CRESPO, MARÍA LAURA BRESER, GABRIEL MORÓN, LIEN DEJAGER, CLAUDE LIBERT, VIRGINIA RIVERO AND MARIANA MACCIONI

Hvar

Otro; 16 International summer school on Immunology; 2011

Federation of European Biochemical Society (FEBS)

Administration of Toll like receptor (TLRs) ligands has always been considered a valuable tool to promote anticancer immunity. Recently, functional TLRs were found to be expressed in cancer cells but their significance remains controversial. B16 murine melanoma cells stimulated in vitro with a TLR4-ligand (LPS-B16), prior to their inoculation into TLR4 deficient mice (TLR4lps-del), induce smaller tumors than those induced by non-stimulated B16 cells. The apoptosis/proliferation balance of the cells is not modified and the effect is lost in athymic nude mice. The same effect was also observed in the MB49 bladder and TRAMPC2 prostate cancer models. Here, we investigate which mechanisms could be taking place in this phenomenon. We have identified interferon β, produced by TLR4-activated tumor cells as an important mediator of these effects. Transcriptional analysis shows that TLR4 triggering on B16 cells induces changes in the expression of type I IFN and type I IFN related genes. Moreover, culture supernatants from LPS-B16 cells improve the maturation of TLR4lps-del bone marrow derived dendritic cells (BMDCs), up-regulating the expression of IL12 and co-stimulatory molecules. This effect is impaired when an anti-IFNβ neutralizing antibody is added. Also, the inhibition of tumor growth observed in LPS-B16 tumors is abrogated in mice lacking the IFNAR1 subunit of the type I IFN receptor. Our results show that tumor cells can be induced through the TLR4 pathway to produce IFNβ and positively contribute to the antitumoral immune response.