Oncotarget

Research Papers:

Prognostic and therapeutic insights into MIF, DDT, and CD74 in melanoma

Caroline Naomi Valdez, Gabriela Athziri Sánchez-Zuno, Lais Osmani, Wael Ibrahim, Anjela Galan, Antonietta Bacchiocchi, Ruth Halaban, Rajan P. Kulkarni, Insoo Kang, Richard Bucala and Thuy Tran _

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Oncotarget. 2024; 15:507-520. https://doi.org/10.18632/oncotarget.28615

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Abstract

Caroline Naomi Valdez1, Gabriela Athziri Sánchez-Zuno2, Lais Osmani2, Wael Ibrahim3, Anjela Galan3, Antonietta Bacchiocchi3, Ruth Halaban3, Rajan P. Kulkarni4,5,6,7, Insoo Kang1,2, Richard Bucala1,2,9 and Thuy Tran1,8,9

1 School of Medicine, Yale University, New Haven, CT 06520, USA

2 Department of Medicine, Section of Rheumatology, Allergy and Immunology, Yale University, New Haven, CT 06520, USA

3 Department of Dermatology, Yale University, New Haven, CT 06520, USA

4 Department of Dermatology, Oregon Health and Science University, Portland, OR 97239, USA

5 Cancer Early Detection Advanced Research Center (CEDAR), Portland, OR 97239, USA

6 Knight Cancer Institute, Oregon Health and Science University, Portland, OR 97239, USA

7 Department of Veterans Affairs Portland Health Care System, Operative Care Division, U.S. Portland, OR 97239, USA

8 Department of Medicine, Section of Medical Oncology, Yale University, New Haven, CT 06520, USA

9 Yale Cancer Center, Yale University, New Haven, CT 06520, USA

Correspondence to:

Thuy Tran, email: [email protected]

Keywords: MIF; DDT; melanoma; immune checkpoint inhibition; cancer transcriptomics

Received: May 16, 2024     Accepted: July 08, 2024     Published: July 19, 2024

Copyright: © 2024 Valdez et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

ABSTRACT

Macrophage Migration Inhibitory Factor (MIF) and its homolog D-dopachrome Tautomerase (DDT) have been implicated as drivers of tumor progression across a variety of cancers. Recent evidence suggests MIF as a therapeutic target in immune checkpoint inhibition (ICI) resistant melanomas, however clinical evidence of MIF and particularly of DDT remain limited. This retrospective study analyzed 97 patients treated at Yale for melanoma between 2002–2020. Bulk-RNA sequencing of patient tumor samples from the Skin Cancer SPORE Biorepository was used to evaluate for differential gene expression of MIF, DDT, CD74, and selected inflammatory markers, and gene expression was correlated with patient survival outcomes. Our findings revealed a strong correlation between MIF and DDT levels, with no statistically significant difference across common melanoma mutations and subtypes. Improved survival was associated with lower MIF and DDT levels and higher CD74:MIF and CD74:DDT levels. High CD74:DDT and CD74:MIF levels were also associated with enrichment of infiltrating inflammatory cell markers. These data suggest DDT as a novel target in immune therapy. Dual MIF and DDT blockade may provide synergistic responses in patients with melanoma, irrespective of common mutations, and may overcome ICI resistance. These markers may also provide prognostic value for further biomarker development.


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