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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

MIF inhibition as a strategy for overcoming resistance to immune checkpoint blockade therapy in melanoma

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Author(s):
de Azevedo, Ricardo A. [1, 2] ; Shoshan, Einav [1] ; Whang, Shanzhi [1] ; Markel, Gal [3] ; Jaiswal, Ashvin R. [4, 5] ; Liu, Arthur [4, 5] ; Curran, Michael A. [5] ; Travassos, Luiz R. [2] ; Bar-Eli, Menashe [1]
Total Authors: 9
Affiliation:
[1] Univ Texas MD Anderson Canc Ctr, Dept Canc Biol, Houston, TX 77030 - USA
[2] Fed Univ Sao Paulo UNIFESP, Dept Microbiol Immunol & Parasitol, Expt Oncol Unit UNONEX, Sao Paulo - Brazil
[3] Sheba Med Ctr, Ella Lemelbaum Inst Immunooncol, Tel Hashomer - Israel
[4] Univ Texas MD Anderson Canc Ctr, Dept Immunol, Houston, TX 77030 - USA
[5] MD Anderson Canc Ctr UT Hlth, Grad Sch Biomed Sci, Houston, TX - USA
Total Affiliations: 5
Document type: Journal article
Source: ONCOIMMUNOLOGY; v. 9, n. 1 2020.
Web of Science Citations: 0
Abstract

Immune checkpoint blockade (ICB) has demonstrated an impressive outcome in patients with metastatic melanoma, yet, durable complete response; even with Ipilimumab/Nivolumab combo are under 30%. Primary and acquired resistance in response to ICB is commonly due to a tumor immune escape mechanism dictated by the tumor microenvironment (TME). Macrophage Migratory Inhibition Factor (MIF) has emerged as an immunosuppressive factor secreted in the TME. We have previously demonstrated that blockade of the MIF-CD74 signaling on macrophages and dendritic cells restored the anti-tumor immune response against melanoma. Here, we report that inhibition of the MIF-CD74 axis combined with ipilimumab could render resistant melanoma to better respond to anti-CTLA-4 treatment. We provide evidence that blocking the MIF-CD74 signaling potentiates CD8+ T-cells infiltration and drives pro-inflammatory M1 conversion of macrophages in the TME. Furthermore, MIF inhibition resulted in reprogramming the metabolic pathway by reducing lactate production, HIF-1 alpha and PD-L1 expression in the resistant melanoma cells. Melanoma patient data extracted from the TCGA database supports the hypothesis that high MIF expression strongly correlates with poor response to ICB therapy. Our findings provide a rationale for combining anti-CTLA-4 with MIF inhibitors as a potential strategy to overcome resistance to ICB therapy in melanoma, turning a ``cold{''} tumor into a ``hot{''} one mediated by the activation of innate immunity and reprogramming of tumor metabolism and reduced PD-L1 expression in melanoma cells. (AU)

FAPESP's process: 17/09393-6 - Validation of novel peptides potentially inhibitory of the MIF/CD74 axis as a strategy for reversing the tumor microenvironment immunotolerance: a preclinical approach for the treatment to metastatic melanoma
Grantee:Ricardo Alexandre de Azevedo
Support type: Scholarships in Brazil - Post-Doctorate
FAPESP's process: 18/18385-0 - Studying the impact of miR-451 on MIF-induced immunosuppression in metastatic melanoma
Grantee:Ricardo Alexandre de Azevedo
Support type: Scholarships abroad - Research Internship - Post-doctor