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Myeloid-derived suppressor cells impede T cell functionality and promote Th17 differentiation in oral squamous cell carcinoma

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Abstract

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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Abbreviations

AICD:

Activation-induced cell death

Arg-1:

Arginase-1

C/EBPα/β:

CCAAT/enhancer-binding protein alpha/beta

cAMP:

Adenosine monophosphate

CFSE:

Carboxyfluorescein succinimidyl ester

cGMP:

Cyclic guanosine monophosphate

COX-2:

Cyclooxygenase-2

HIs:

Healthy individuals

HNSCC:

Head and neck squamous cell carcinoma

IDO:

2,3-Dioxygenase

IL-10:

Interleukin 10

L-NMMA:

NG-Methyl-l-arginine acetate

MDSCs:

Myeloid-derived suppressor cells

MLR:

Mixed leukocyte reaction

NOS:

Nitric oxide synthase

NS-398:

N-(2-Cyclohexyloxy-4-nitrophenyl) methanesulfonamide

OC:

Oral cancer

OSCC:

Oral squamous cell carcinoma

PBMCs:

Peripheral blood mononuclear cells

PD-L1/2:

Programmed death receptor ligand ½

STAT3:

Signal transducer and activator of transcription 3

TCR:

T cell receptor

Tregs:

T regulatory cells

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Funding

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.

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Author notes

  1. Asif A. Dar and Rushikesh S. Patil have contributed equally to this manuscript.

Authors and Affiliations

  1. Chiplunkar Lab, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai, Maharashtra, 410210, India

    Asif A. Dar, Rushikesh S. Patil, Trupti N. Pradhan & Shubhada V. Chiplunkar

  2. Homi Bhabha National Institute, Anushaktinagar, Mumbai, Maharashtra, 400094, India

    Asif A. Dar, Rushikesh S. Patil & Shubhada V. Chiplunkar

  3. Tata Memorial Hospital, Tata Memorial Centre, Dr. E. Borges Road, Parel, Mumbai, Maharashtra, 400012, India

    Devendra A. Chaukar & Anil K. D’Cruz

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  1. Asif A. Dar
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  4. Devendra A. Chaukar
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Contributions

SVC, AAD and RSP conceived and designed the study. AAD, RSP, TNP and SVC acquired, analyzed and interpreted the data and contributed to the drafting of the manuscript. SVC critically revised the manuscript, obtained the funding and supervised the study. AAD and RSP contributed to the statistical analysis. DAC and AKD provided the patient samples.

Corresponding author

Correspondence to Shubhada V. Chiplunkar.

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Conflict of interest

The authors declare that they have no conflict of interest.

Ethical standards

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).

Informed consent

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

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