Antonietta Bacchiocchi

Abstract A mass spectrometry analysis was performed using serum from patients receiving checkpoint inhibitors to define baseline protein signatures associated with outcome in metastatic melanoma. Pretreatment serum was obtained from a development set of 119 melanoma patients on a trial of nivolumab with or without a multipeptide vaccine and from patients receiving pembrolizumab, nivolumab, ipilimumab, or both nivolumab and ipilimumab. Spectra were obtained using matrix-assisted laser desorption/ionization time of flight mass spectrometry. These data combined with clinical data identified patients with better or worse outcomes. The test was applied to five independent patient cohorts treated with checkpoint inhibitors and its biology investigated using enrichment analyses. A signature consisting of 209 proteins or peptides was associated with progression-free and overall survival in a multivariate analysis. The test performance across validation cohorts was consistent with the development set results. A pooled analysis, stratified by set, demonstrated a significantly better overall survival for “sensitive” relative to “resistant” patients, HR = 0.15 (95% confidence interval: 0.06–0.40, P < 0.001). The test was also associated with survival in a cohort of ipilimumab-treated patients. Test classification was found to be associated with acute phase reactant, complement, and wound healing pathways. We conclude that a pretreatment signature of proteins, defined by mass spectrometry analysis and machine learning, predicted survival in patients receiving PD-1 blocking antibodies. This signature of proteins was associated with acute phase reactants and elements of wound healing and the complement cascade. This signature merits further study to determine if it identifies patients who would benefit from PD-1 blockade. Cancer Immunol Res; 6(1); 79–86. ©2017 AACR.

// Caroline Naomi Valdez 1 , Gabriela Athziri Sánchez-Zuno 2 , Lais Osmani 2 , Wael Ibrahim 3 , Anjela Galan 3 , Antonietta Bacchiocchi 3 , Ruth Halaban 3 , Rajan P. Kulkarni 4 , 5 , 6 , 7 , Insoo Kang 1 , 2 , Richard Bucala 1 , 2 , 9 and Thuy Tran 1 , 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: thuy.tran@yale.edu 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.