Oral tumor microenvironment is characterized by chronic inflammation signified with infiltrating leukocytes and soluble mediators which cause immune suppression. However, how immunosuppressive cells like myeloid-derived suppressor cells (MDSCs) maintain the immunosuppressive tumor microenvironment and influence T cell function in oral squamous cell carcinoma (OSCC) patients remains poorly understood. In the present study, we found that percentages of MDSCs were higher in oral cancer patients compared to healthy individuals and correlated with cancer stage. Monocytic MDSCs (M-MDSCs) were prevalent in the periphery, while granulocytic/polymorphonuclear subset dominated the tumor compartment. M-MDSCs suppressed the lymphocyte proliferation and decreased the CD3-ζ (zeta) chain expression and interferon gamma production. The percentage of M-MDSCs in peripheral blood correlated inversely with CD3-ζ chain expression in T cells of these patients. Interleukin 6 (IL-6)-induced phosphorylated STAT3-regulated programmed cell death ligand 1, CCAAT/enhancer-binding proteins alpha and beta and Interleukin 10 expression in MDSCs. MDSCs inhibited TGF-β-driven generation of induced regulatory T cells in vitro. M-MDSCs secreted interleukins IL-6, IL-1β, IL-23 and PGE2 and facilitated T-helper 17 (Th17) cell differentiation which utilizes nitric oxide synthase and cyclooxygenase 2 enzyme activity. Interestingly, OSCC patients showed increased levels of Th17 cells in peripheral blood and tumor tissue. Thus, increased frequency of MDSCs, Th17 cells and decreased expression of CD3-ζ chain portray T cell tolerance and chronic inflammatory state facilitating tumor growth.
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Activation-induced cell death
CCAAT/enhancer-binding protein alpha/beta
Carboxyfluorescein succinimidyl ester
Cyclic guanosine monophosphate
Head and neck squamous cell carcinoma
Myeloid-derived suppressor cells
Mixed leukocyte reaction
Nitric oxide synthase
Oral squamous cell carcinoma
Peripheral blood mononuclear cells
Programmed death receptor ligand ½
Signal transducer and activator of transcription 3
T cell receptor
T regulatory cells
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The work was supported by the Department of Biotechnology, India, grant (BT/PR8245/MED/30/985/2013) to Shubhada V Chiplunkar. We thank Council for Scientific and Industrial research (CSIR) for providing fellowship to Asif A Dar. Rushikesh S Patil was supported by the Department of Science and Technology INSPIRE Faculty Grant.
Conflict of interest
The authors declare that they have no conflict of interest.
The study was approved by the “Tata Memorial Centre—Institutional Ethics Committee III (ACTREC IEC)” (IEC study number # 105; approved on 07/03/2013). All procedures performed in the study involving human samples were according to the ethical standards and approvals of Institutional Ethics Committee which is guided in its reflection, advice and decision by the ethical principles expressed in the “Declaration of Helsinki” and CFR 45 (US FDA).
All participants including OSCC patients and HI voluntarily participated in the study. The participants agreed to provide their samples (peripheral blood or tumor tissue collected after surgery) and related data for research purpose and scientific publication after signing written informed consent before sample collection. The format of the consent form was approved by the Institution Ethics Committee (IEC). The peripheral blood of the participants was collected with the help of trained phlebotomists. Tumor tissues of the patients were provided by the tumor tissue repository of ACTREC-Tata Memorial Centre.
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Dar, A.A., Patil, R.S., Pradhan, T.N. et al. Myeloid-derived suppressor cells impede T cell functionality and promote Th17 differentiation in oral squamous cell carcinoma. Cancer Immunol Immunother 69, 1071–1086 (2020). https://doi.org/10.1007/s00262-020-02523-w
- Oral cancer
- Myeloid-derived suppressor cells
- T regulatory cells
- Th17 cells
- TCR CD3-ζ chain