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Interfering with MIF-CD74 signalling on macrophages and dendritic cells with a peptide-based approach restores the immune response against metastatic melanoma

Carlos R. Figueiredo, Ricardo A. Azevedo, Sasha Mousdell, Pedro T. Resende-Lara, Lucy Ireland, Almudena Santos, Natalia Girola, Rodrigo L.O.R. Cunha, Michael C. Schmid, Luciano Polonelli, Luiz R. Travassos, View ORCID ProfileAinhoa Mielgo
doi: https://doi.org/10.1101/248807
Carlos R. Figueiredo
1Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, United Kingdom.
2Experimental Oncology Unit (UNONEX), Department of Microbiology, Immunology and Parasitology, Federal University of São Paulo (UNIFESP), São Paulo, SP - Brazil.
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Ricardo A. Azevedo
2Experimental Oncology Unit (UNONEX), Department of Microbiology, Immunology and Parasitology, Federal University of São Paulo (UNIFESP), São Paulo, SP - Brazil.
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Sasha Mousdell
1Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, United Kingdom.
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Pedro T. Resende-Lara
3Laboratory of Computational Biology and Bioinformatics, Federal University of ABC, Santo André, São Paulo, SP, Brazil.
4Laboratoire de Biologie et Pharmacologie Appliquées (LBPA), UMR 8113, Ecole Normale Supérieure, Cachan, France.
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Lucy Ireland
1Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, United Kingdom.
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Almudena Santos
1Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, United Kingdom.
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Natalia Girola
2Experimental Oncology Unit (UNONEX), Department of Microbiology, Immunology and Parasitology, Federal University of São Paulo (UNIFESP), São Paulo, SP - Brazil.
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Rodrigo L.O.R. Cunha
5Chemical Biology Laboratory, Natural and Human Sciences Center, Federal University of ABC, Santo André, SP, Brazil.
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Michael C. Schmid
1Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, United Kingdom.
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Luciano Polonelli
6Unit of Biomedical, Biotechnological and Translational Sciences, Department of Medicine and Surgery, Universitá degli Studi di Parma, Parma, Italy.
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Luiz R. Travassos
2Experimental Oncology Unit (UNONEX), Department of Microbiology, Immunology and Parasitology, Federal University of São Paulo (UNIFESP), São Paulo, SP - Brazil.
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  • For correspondence: travassos@unifesp.br
Ainhoa Mielgo
1Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, United Kingdom.
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  • ORCID record for Ainhoa Mielgo
  • For correspondence: amielgo@liverpool.ac.uk
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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. Immunotherapies that boost the activity of effector T cells have shown a remarkable success in melanoma treatment. Patients, however, can develop resistance to such therapies by mechanisms that include the establishment of an immune suppressive tumour microenvironment. Understanding how metastatic melanoma cells suppress the immune system is vital to develop effective immunotherapies against this disease. In this study, we find that the innate immune cells, macrophages and dendritic cells are suppressed in metastatic melanoma. The Ig-CDR-based peptide C36L1 is able to restore macrophages and dendritic cells’ immunogenic functions and to inhibit metastatic growth in vivo. Mechanistically, we found that C36L1 interferes with the MIF-CD74 tumour-innate immune cells immunosuppressive signalling pathway and thereby restores an effective anti-tumour immune response. C36L1 directly binds to CD74 on macrophages and dendritic cells, disturbing CD74 structural dynamics and inhibiting MIF signalling through CD74. Our findings suggest that interfering with MIF-CD74 immunosuppressive signalling in macrophages and dendritic cells using peptide-based immunotherapy can restore the anti-tumour immune response in metastatic melanoma. Our study provides the rationale for further development of peptide-based therapies to restore the anti-tumour immune response.

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Posted January 16, 2018.
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Interfering with MIF-CD74 signalling on macrophages and dendritic cells with a peptide-based approach restores the immune response against metastatic melanoma
Carlos R. Figueiredo, Ricardo A. Azevedo, Sasha Mousdell, Pedro T. Resende-Lara, Lucy Ireland, Almudena Santos, Natalia Girola, Rodrigo L.O.R. Cunha, Michael C. Schmid, Luciano Polonelli, Luiz R. Travassos, Ainhoa Mielgo
bioRxiv 248807; doi: https://doi.org/10.1101/248807
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Interfering with MIF-CD74 signalling on macrophages and dendritic cells with a peptide-based approach restores the immune response against metastatic melanoma
Carlos R. Figueiredo, Ricardo A. Azevedo, Sasha Mousdell, Pedro T. Resende-Lara, Lucy Ireland, Almudena Santos, Natalia Girola, Rodrigo L.O.R. Cunha, Michael C. Schmid, Luciano Polonelli, Luiz R. Travassos, Ainhoa Mielgo
bioRxiv 248807; doi: https://doi.org/10.1101/248807

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