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

Ricardo A. de Azevedo, Einav Shoshan, Shanzhi Whang, Gal Markel, Ashvin R. Jaiswal, Arthur Liu, Michael A. Curran, Luiz R. Travassos, Menashe Bar-Eli

Research output: Contribution to journalArticlepeer-review

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-1α 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.

Original languageEnglish
Article number1846915
JournalOncoImmunology
Volume9
Issue number1
DOIs
StatePublished - 2020
Externally publishedYes

Keywords

  • Macrophage Migratory Inhibition Factor
  • Melanoma
  • combined modality therapy
  • immune checkpoint therapy
  • tumor microenvironment

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