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

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

Author Figueiredo, Carlos Rogerio Autor UNIFESP Google Scholar
Azevedo, Ricardo Alexandre de Autor UNIFESP Google Scholar
Mousdell, Sasha Google Scholar
Resende-Lara, Pedro T. Google Scholar
Ireland, Lucy Google Scholar
Santos, Almudena Google Scholar
Girola, Natalia Autor UNIFESP Google Scholar
Cunha, Rodrigo L. O. R. Google Scholar
Schmid, Michael C. Google Scholar
Polonelli, Luciano Google Scholar
Travassos, Luiz Rodolpho Autor UNIFESP Google Scholar
Mielgo, Ainhoa Google Scholar
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.
Keywords metastatic melanoma
dendritc cells
immune response
peptide-based immunotherapy
macrophage migration inhibitory factor
Language English
Sponsor Sao Paulo Research Foundation FAPESP
Sir Henry Dale research fellowship - Wellcome Trust
Royal Society
Grant number FAPESP: 2015/23898-8
Royal Society: 102521/Z/13/Z
Date 2018
Published in Frontiers In Immunology. Lausanne, v. 9, p. -, 2018.
ISSN 1664-3224 (Sherpa/Romeo, impact factor)
Publisher Frontiers Media Sa
Extent -
Access rights Open access Open Access
Type Article
Web of Science ID WOS:000432830000001

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