Date of Award

January 2025

Document Type

Open Access Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Thuy Tran

Abstract

Macrophage Migration Inhibitory Factor (MIF) and its homolog D-dopachrome Tautomerase (DDT) are pro-inflammatory cytokines implicated in tumor progression across multiple cancers. Both MIF and DDT act through canonical CD74 and non-canonical CXCR2/4/7 signaling pathways, which contribute to immune suppression and tumor progression. Elevated MIF levels are associated with metastasis and poor prognosis in HNC and contribute to immune checkpoint inhibitor (ICI) resistance in melanoma. DDT’s role in cancer is not well understood. This study aims to evaluate the expression and therapeutic potential of MIF and DDT inhibition, focusing on their ability to modulate immune responses and improve survival outcomes as novel therapeutic targets. We focused on HNC and melanoma for our studies given the preclinical data implicating MIF in the pathogenesis of these malignancies. In the HNC arm of our study, we utilized immune-sensitive (MOC1) and immune-resistant (MOC2) mouse oropharyngeal carcinoma tumor in vivo models to assess the efficacy of dual MIF and DDT inhibition. Genetically modified mice engineered to express human low (CATT5) and high (CATT7) MIF expression promoters were also used to evaluate the impact of MIF levels on HNC progression and survival. We also performed a retrospective analysis of 524 unique bulk RNA sequencing samples from patients with HNC from The Cancer Genome Atlas (TCGA) to correlate tumor cytokine expression with patient outcomes. We evaluated how MIF, DDT, and CD74 expression correlate with survival outcomes, and how expression changes when stratified by HPV status. For the melanoma arm of this project, we obtained bulk RNA sequencing from 97 patient-derived tumor samples collected by the Yale Skin Cancer SPORE Biorepository from 2002-2020. Gene expression of MIF, DDT, CD74, and inflammatory markers were correlated with patient survival outcomes. In murine models of HNC, dual inhibition of MIF and DDT with anti-PD-1/cisplatin significantly delayed tumor growth and improved survival compared to cisplatin/anti-PD-1 treatment alone. Monotherapy with anti-MIF or anti-DDT delayed tumor growth but was less effective than combination treatment. Additionally, MOC2-bearing mice did not benefit from anti-MIF/anti-DDT therapy. Genetically modified mice with low MIF expression (CATT5) showed better survival than high MIF-expressing (CATT7) mice in MOC1 tumors, while the opposite was observed in MOC2-bearing mice. For HNC, TCGA analysis revealed significantly elevated MIF and DDT expression in tumor tissues compared to benign tissues, with higher expression linked to poorer survival outcomes. In the Yale melanoma cohort, higher levels of MIF and DDT and lower levels of CD74 were correlated with worse survival. Lower MIF and DDT expression, alongside higher CD74:MIF and CD74:DDT ratios, correlated with improved survival in melanoma patients. Specifically, high CD74:MIF and CD74:DDT ratios were associated with increased immune cell infiltration. These findings suggest that MIF and DDT are promising therapeutic targets, particularly in melanoma and HNC. Dual inhibition of MIF and DDT not only suppresses tumor growth but also enhances immune cell infiltration, reshaping the tumor microenvironment (TME). These results support dual MIF and DDT inhibition as a synergistic approach to overcome treatment resistance in melanoma and HNC. The identification of MIF and DDT as therapeutic targets opens new avenues for combination therapies that could benefit patients with resistant cancers. Further investigation is needed to optimize patient stratification and refine therapeutic combinations to maximize clinical benefits.

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This is an Open Access Thesis.

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