MIF inhibition as a strategy for overcoming resistance to immune checkpoint blockade therapy in melanoma
| Autor: | Michael A. Curran, Shanzhi Whang, Ricardo A. de Azevedo, Menashe Bar-Eli, Luiz R. Travassos, Gal Markel, Einav Shoshan, Arthur Liu, Ashvin R. Jaiswal |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
combined modality therapy Immunology chemical and pharmacologic phenomena Ipilimumab 03 medical and health sciences 0302 clinical medicine Immune system Tumor Microenvironment Humans Immunology and Allergy Medicine Immune Checkpoint Inhibitors Macrophage Migration-Inhibitory Factors Melanoma Macrophage Migratory Inhibition Factor RC254-282 Original Research Tumor microenvironment Innate immune system business.industry Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC581-607 medicine.disease Immune checkpoint immune checkpoint therapy Blockade Intramolecular Oxidoreductases 030104 developmental biology Oncology 030220 oncology & carcinogenesis Cancer research Immunologic diseases. Allergy Nivolumab business Research Article medicine.drug |
| Zdroj: | Oncoimmunology article-version (VoR) Version of Record OncoImmunology, Vol 9, Iss 1 (2020) |
| ISSN: | 2162-402X |
| DOI: | 10.1080/2162402x.2020.1846915 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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