Blockade of MIF-CD74 Signalling on Macrophages and Dendritic Cells Restores the Antitumour Immune Response Against Metastatic Melanoma

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dc.contributor.author Figueiredo, Carlos Rogerio [UNIFESP]
dc.contributor.author Azevedo, Ricardo Alexandre de [UNIFESP]
dc.contributor.author Mousdell, Sasha
dc.contributor.author Resende-Lara, Pedro T.
dc.contributor.author Ireland, Lucy
dc.contributor.author Santos, Almudena
dc.contributor.author Girola, Natalia [UNIFESP]
dc.contributor.author Cunha, Rodrigo L. O. R.
dc.contributor.author Schmid, Michael C.
dc.contributor.author Polonelli, Luciano
dc.contributor.author Travassos, Luiz Rodolpho [UNIFESP]
dc.contributor.author Mielgo, Ainhoa
dc.date.accessioned 2018-07-26T12:18:46Z
dc.date.available 2018-07-26T12:18:46Z
dc.date.issued 2018
dc.identifier http://dx.doi.org/10.3389/fimmu.2018.01132
dc.identifier.citation Frontiers In Immunology. Lausanne, v. 9, p. -, 2018.
dc.identifier.issn 1664-3224
dc.identifier.uri http://repositorio.unifesp.br/handle/11600/46031
dc.description.abstract Mounting an effective immune response against cancer requires the activation of innate and adaptive immune cells. Metastatic melanoma is the most aggressive form of skin cancer. While immunotherapies have shown a remarkable success in melanoma treatment, patients develop resistance by mechanisms that include the establishment of an immune suppressive tumor microenvironment. Thus, understanding how metastatic melanoma cells suppress the immune system is vital to develop effective immunotherapies against this disease. In this study, we find that macrophages (MOs) and dendritic cells (DCs) are suppressed in metastatic melanoma and that the Ig-CDR-based peptide C36L1 is able to restore MOs and DCs' antitumorigenic and immunogenic functions and to inhibit metastatic growth in lungs. Specifically, C36L1 treatment is able to repolarize M2-like immunosuppressive MOs into M1-like antitumorigenic MOs, and increase the number of immunogenic DCs, and activated cytotoxic T cells, while reducing the number of regulatory T cells and monocytic myeloid-derived suppressor cells in metastatic lungs. Mechanistically, we find that C36L1 directly binds to the MIF receptor CD74 which is expressed on MOs and DCs, disturbing CD74 structural dynamics and inhibiting MIF signaling on these cells. Interfering with MIF-CD74 signaling on MOs and DCs leads to a decrease in the expression of immunosuppressive factors from MOs and an increase in the capacity of DCs to activate cytotoxic T cells. Our findings suggest that interfering with MIF-CD74 immunosuppressive signaling in MOs and DCs, using peptide-based immunotherapy can restore the antitumor immune response in metastatic melanoma. Our study provides the rationale for further development of peptide-based therapies to restore the antitumor immune response in metastatic melanoma. en
dc.description.sponsorship Sao Paulo Research Foundation FAPESP
dc.description.sponsorship Sir Henry Dale research fellowship - Wellcome Trust
dc.description.sponsorship Royal Society
dc.format.extent -
dc.language.iso eng
dc.publisher Frontiers Media Sa
dc.rights Acesso aberto
dc.subject metastatic melanoma en
dc.subject macrophages en
dc.subject dendritc cells en
dc.subject immune response en
dc.subject peptide-based immunotherapy en
dc.subject macrophage migration inhibitory factor en
dc.subject CD74 en
dc.title Blockade of MIF-CD74 Signalling on Macrophages and Dendritic Cells Restores the Antitumour Immune Response Against Metastatic Melanoma en
dc.type Artigo
dc.description.affiliation Univ Liverpool, Dept Mol & Clin Canc Med, Liverpool, Merseyside, England
dc.description.affiliation Fed Univ Sao Paulo UNIFESP, Dept Microbiol Immunol & Parasitol, Expt Oncol Unit UNONEX, Sao Paulo, Brazil
dc.description.affiliation Fed Univ ABC, Lab Computat Biol & Bioinformat, Santo Andre, Brazil
dc.description.affiliation Ecole Normale Super, UMR 8113, LBPA, Cachan, France
dc.description.affiliation Fed Univ ABC, Nat & Human Sci Ctr, Chem Biol Lab, Santo Andre, Brazil
dc.description.affiliation Univ Parma, Dept Med & Surg, Unit Biomed Biotechnol & Translat Sci, Parma, Italy
dc.description.affiliationUnifesp Fed Univ Sao Paulo UNIFESP, Dept Microbiol Immunol & Parasitol, Expt Oncol Unit UNONEX, Sao Paulo, Brazil
dc.description.sponsorshipID FAPESP: 2015/23898-8
dc.description.sponsorshipID Royal Society: 102521/Z/13/Z
dc.identifier.file WOS000432830000001.pdf
dc.identifier.doi 10.3389/fimmu.2018.01132
dc.description.source Web of Science
dc.identifier.wos WOS:000432830000001



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