Myeloid-derived MIF is a central regulator of MDSC-driven T-cell dysfunction in head and neck squamous cell carcinoma.

Authors

Suvekshya Shrestha, Felipe Lamenza, Natalie Kazmierowicz, Kishan Kumar Nyati, Sushmitha Jagadeesha, Ravi Ramalingam, Reegan Kehres, Puja Upadhaya, Arham Siddiqui, Shaheer Masood, Massar Yade, Sonali Dasari, Steve Oghumu

Published in

Oncoimmunology. Volume 15. Issue 1. Pages 2719293. Dec 31, 2026. Epub Aug 18, 2026.

Abstract

Head and neck squamous cell carcinoma (HNSCC) exhibits a profoundly immunosuppressive tumor microenvironment (TME) enriched for myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), and dysfunctional CD8⁺ T cells, limiting therapeutic benefit from immune checkpoint blockade. Macrophage migration inhibitory factor (MIF) is elevated in HNSCC and linked to poor outcomes, yet the cellular source and functional role of tumor-promoting MIF in shaping antitumor immunity remain unclear.
We used a myeloid-specific MIF knockout mouse (mMIF KO) in an orthotopic MOC2 HNSCC model and evaluated immune function using ex vivo co-cultures of tumor-derived MDSCs with naïve T cells under Treg-skewing, basal, or Th1-polarizing conditions.
Myeloid-restricted MIF deletion significantly reduced tumor growth and increased CD8⁺ T cell infiltration, accompanied by reduced CTLA4, TIGIT, and TIM3 expression, with elevated PD1 consistent with antigen-engaged effector activation. High-dimensional immune profiling revealed expansion of cytotoxic CD8⁺ T cell states (GranzymeB^hi/Perforin^hi) and contraction of IL10-producing CD4⁺ regulatory (Tr1-like) populations, findings corroborated by decreased intratumoral CD4⁺FoxP3⁺Tregs. Within the myeloid compartment, MIF deletion selectively depleted polymorphonuclear MDSCs (PMN-MDSCs), including CSF1R^hi and PD-L1^hi subsets. Functionally, tumor-derived MDSCs lacking MIF showed impaired capacity to induce Tregs and to promote CD8⁺ T cell exhaustion in ex vivo co-cultures, effects partially overcome by TGFβ/Th1-polarizing signals.
These findings identify myeloid-derived MIF as a central regulator of the MDSC-Treg-CD8⁺ axis in HNSCC and support myeloid-targeted MIF inhibition as a strategy to reprogram the TME and enhance responses to immune checkpoint blockade.

PMID:
42612021
Bibliographic data and abstract were imported from PubMed on 19 Aug 2026.

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