763 Therapeutic targeting of the MIF/DDT-CD74 axis in head and neck squamous cell carcinoma (HNSCC) murine models

Background

Head and Neck Squamous Cell Carcinoma (HNSCC) is primarily treated by definitive surgery, often coupled with risk-stratified adjuvant chemotherapy.1 However, surgical interventions pose significant risks, such as speech impairment and dysphagia, highlighting the need for novel pharmacological treatments.2Macrophage Migration Inhibitory Factor (MIF) and its homolog D-Dopachrome Tautomerase (DDT) have been implicated in tumorigenesis in many cancer types through canonical CD74 and non-canonical CXCR2/4/7 signaling pathways.3 In HNSCC, elevated circulating MIF levels correlate with metastasis and poor prognosis; however, DDT has not yet been evaluated.4 5 Furthermore, more research is needed to elucidate the roles of MIF and DDT in HNSCC progression. Thus, we aim to evaluate these cytokines as potential targets in preclinical and clinical models of HNSCC.

Methods

We employed Gene Expression Profiling Interactive Analysis (GEPIA2) and the Tumor Immune Estimation Resource (TIMER2.0), drawing from publicly available TCGA data, to evaluate differential MIF and DDT expression levels in HNSCC. Additionally, we experimentally injected syngeneic C57BL/6 mice subcutaneously with immune-sensitive mouse oropharyngeal cells (MOC1) and evaluated the effect of the following treatment regimens on tumor growth: anti-MIF, anti-DDT, anti-MIF/anti-DDT, anti-PD-1, Cisplatin, anti-PD1/MIF/DDT, and Cisplatin/anti-MIF/anti-DDT (table 1). Treatment was initiated when tumor sizes reached 50ā€“100 mm3. Endpoint was defined as tumors reaching 400 mm3. Tumor growth between treatment groups was evaluated by analyzing time to endpoint with Kruskal-Wallis testing.

Results

Our findings reveal an overexpression of MIF and DDT in HNSCC tumor samples compared to normal tissue, with higher levels among HNSCC patients correlating with worse overall survival (MIF: p = 0.06; DDT: p = 0.025). No difference in MIF or DDT expression was observed when stratified by HPV status. Furthermore, our murine model demonstrates that all treatment regimens extended time to endpoint compared to wildtype mice (p = 0.0319).

Conclusions

MIF and DDT expression is increased in HNSCC, and blockade of these agents demonstrated slowed tumor growth in our murine models. These data highlight the potential of MIF and DDT as targets for intervention in patients with HNSCC.

References

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  • Kindt N, Preillon J, Kaltner H, Gabius HJ, Chevalier D, Rodriguez A, Johnson BD, Megalizzi V, Decaestecker C, Laurent G, Saussez S. Macrophage migration inhibitory factor in head and neck squamous cell carcinoma: clinical and experimental studies. J Cancer Res Clin Oncol. 2013 May;139(5):727ā€“37. doi: 10.1007/s00432-013-1375-7. Epub 2013 Jan 25. PMID: 23354841.

  • Ethics Approval

    This study was approved by the Yale University Institutional Review Board under (IRB) Protocol 1206010419 and the Institutional Animal Care and Use Committee (IACUC) under Protocol 10992.

    Abstract 763 Table 1

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