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Regular and Young Investigator Award Abstracts
Combination Immunotherapies
763 Therapeutic targeting of the MIF/DDT-CD74 axis in head and neck squamous cell carcinoma (HNSCC) murine models
  1. Caroline N Valdez1,
  2. Gabriela A Sánchez-Zuno1,
  3. Anya Mahajan1,
  4. William Trosch1,
  5. Barbara Burtness1,
  6. Richard Bucala1 and
  7. Thuy Tran1,2
  1. 1Yale School of Medicine, New Haven, CT, USA
  2. 2Yale University, Madison, CT, USA

  • Journal for ImmunoTherapy of Cancer (JITC) preprint. The copyright holder for this preprint are the authors/funders, who have granted JITC permission to display the preprint. All rights reserved. No reuse allowed without permission.

Abstract

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 50–100 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

  1. Bhatia A, Burtness B. Treating head and neck cancer in the age of immunotherapy: a 2023 update. Drugs. 2023 Feb;83(3):217–48. doi: 10.1007/s40265-023-01835-2. Epub 2023 Jan 16. PMID: 36645621.

  2. Nguyen NA, Ringash J. Head and neck cancer survivorship care: a review of the current guidelines and remaining unmet needs. Curr Treat Options Oncol. 2018 Jul 9;19(8):44. doi: 10.1007/s11864-018-0554-9. PMID: 29987676.

  3. Mora Barthelmess R, Stijlemans B, Van Ginderachter JA. Hallmarks of cancer affected by the mif cytokine family. Cancers (Basel). 2023 Jan 6;15(2):395. doi: 10.3390/cancers15020395. PMID: 36672343; PMCID: PMC9856758.

  4. Lechien JR, Nassri A, Kindt N, Brown DN, Journe F, Saussez S. Role of macrophage migration inhibitory factor in head and neck cancer and novel therapeutic targets: a systematic review. Head Neck. 2017 Dec;39(12):2573–84. doi: 10.1002/hed.24939. Epub 2017 Sep 30. PMID: 28963807.

  5. 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):727–37. 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.

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Abstract 763 Table 1
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This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/jitc-2024-SITC2024.0763

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