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

Carlos R Figueiredo,Luiz R Travassos,Sasha Mousdell,Ricardo A Azevedo,Luciano Polonelli,Michael C Schmid,Rodrigo L O R Cunha,Natalia Girola,Almudena Santos,Ainhoa Mielgo,Lucy Ireland,Pedro T Resende-Lara

doi:10.3389/fimmu.2018.01132

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.

Highlights

Cutaneous melanoma is a cancer that develops from melanocytes generally located in the epidermal basal cell layer of the skin
We have previously shown that intraperitoneal injections of the antitumor complementary determining regions (CDRs) peptide C36L1 significantly decrease pulmonary melanoma metastasis in a syngeneic model [24, 25]
These findings suggest that the antitumor effects induced by C36L1 in vivo may result from the peptide ability to stimulate the host immune response

Summary

Introduction

Cutaneous melanoma is a cancer that develops from melanocytes generally located in the epidermal basal cell layer of the skin. At very-early stages, single skin lesions can be promptly excised and the 5-year survival rate of melanoma is 98%. Beyond these stages, melanoma can metastasize to distant organs including lungs, liver, bones, and brain, and the 5-year survival rate in stage IV drastically decreases to 15–20% [1, 2]. To evade the immune response, melanomas often activate negative immune checkpoint regulators (ICRs) such as PD-1 and PD-L1 or CTLA-4 that inhibit effector T cell and function in peripheral tissues or lymph nodes, respectively [6, 7]. DCs and MOs are cells from the innate immune system that are essential for starting and shaping the immune response against any damaged tissue, including cancer [7, 10]

Methods

Results

Conclusion