IFNβ produced by TLR-activated tumor cells is involved in improving the antitumoral immune response

NICOLÁS GONZALO NUÑEZ, VIRGINIA ANDREANI, DAVID ANDRÉS NOCERA, GERARDO GATTI, MARIA INES CRESPO, GABRIEL MORÓN, LIEN DEJAGER#, CLAUDE LIBERT#, VIRGINIA RIVERO AND MARIANA MACCIONI

Dublin

Simposio; The Role of Inflammation during Carcinogenesis; 2012

Administration of Toll like receptor (TLRs) ligands has always been considered a valuable tool to promote anticancer immunity. Recently, f unctional 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 LPS-B16 cells is not modified and the inhibition in tumor growth is lost in athymic nude mice. This phenomenon was also observed in the MB49 bladder and TRAMPC2 prostate cancer models. 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. Likewise, IFN produced by Poly I:C (a TLR3 ligand)- stimulated human cancer cell lines could rescue human monocyte-derived dendritic cells from the immunosuppressive state induced by tumor cell- conditioned medium. Our results show that tumor cells can be induced through the TLR pathway to produce IFNβ and positively contribute to the antitumoral immune response.