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Novel Effector Phenotype of Tim-3+ Regulatory T Cells Leads to Enhanced Suppressive Function in Head and Neck Cancer Patients.

ABSTRACT: Purpose: Regulatory T (Treg) cells are important suppressive cells among tumor-infiltrating lymphocytes (TIL). Treg cells express the well-known immune checkpoint receptor PD-1, which is reported to mark "exhausted" Treg with lower suppressive function. T-cell immunoglobulin mucin (Tim)-3, a negative regulator of Th1 immunity, is expressed by a sizeable fraction of TIL Tregs, but the functional status of Tim-3+ Tregs remains unclear.Experimental Design: CD4+CTLA-4+CD25high Treg cells were sorted from freshly excised head and neck squamous cell carcinoma (HNSCC) TIL based on Tim-3 expression. Functional and phenotypic features of these Tim-3+ and Tim-3- TIL Tregs were tested by in vitro suppression assays and multi-color flow cytometry. Gene-expression profiling and NanoString analysis of Tim-3+ TIL Treg were performed. A murine HNSCC tumor model was used to test the effect of anti-PD-1 immunotherapy on Tim-3+ Treg.Results: Despite high PD-1 expression, Tim-3+ TIL Treg displayed a greater capacity to inhibit naïve T-cell proliferation than Tim-3- Treg. Tim-3+ Treg from human HNSCC TIL also displayed an effector-like phenotype, with more robust expression of CTLA-4, PD-1, CD39, and IFN-? receptor. Exogenous IFN-? treatment could partially reverse the suppressive function of Tim-3+ TIL Treg. Anti-PD-1 immunotherapy downregulated Tim-3 expression on Tregs isolated from murine HNSCC tumors, and this treatment reversed the suppressive function of HNSCC TIL Tregs.Conclusions: Tim-3+ Treg are functionally and phenotypically distinct in HNSCC TIL, and are highly effective at inhibiting T-cell proliferation despite high PD-1 expression. IFN-? induced by anti-PD-1 immunotherapy may be beneficial by reversing Tim-3+ Treg suppression. Clin Cancer Res; 24(18); 4529-38. ©2018 AACR.

SUBMITTER: Liu Z

PROVIDER: S-EPMC6139056 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Novel Effector Phenotype of Tim-3+ Regulatory T Cells Leads to Enhanced Suppressive Function in Head and Neck Cancer Patients.

Liu Zhuqing Z McMichael Elizabeth L EL Shayan Gulidanna G Li Jing J Chen Kevin K Srivastava Raghvendra R Kane Lawrence P LP Lu Binfeng B Ferris Robert L RL

Clinical cancer research : an official journal of the American Association for Cancer Research 20180430 18

Purpose: Regulatory T (Treg) cells are important suppressive cells among tumor-infiltrating lymphocytes (TIL). Treg cells express the well-known immune checkpoint receptor PD-1, which is reported to mark "exhausted" Treg with lower suppressive function. T-cell immunoglobulin mucin (Tim)-3, a negative regulator of Th1 immunity, is expressed by a sizeable fraction of TIL Tregs, but the functional status of Tim-3+ Tregs remains unclear.Experimental Design: CD4+CT ...[more]

PMID: 29712685

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Project description:Recent evidence suggests that cancer stem cells (CSCs), a small population of cancer cells that are highly tumourigenic, capable of self-renewal and have the ability to differentiate into cells that constitute the tumor, are the "drivers" of local recurrence and metastatic spread and may be associated with resistant to conventional therapy. The objectives of the study are to identify and characterize two head and neck cancer cell lines with regard CD44high/CD133high/CD117high profile (CSCs) and CD44low/CD133low/CD117low profile (Non-CSCs); to investigate the influence of chemotherapy treatment in CSCs and compare with Non-CSCs; to evaluate CD44 and EGFR gene expression in CSCs. Fluorescent-activated cell sorting (FACS) using specific cell surface marker combination (CD44, CD117 and CD133) was performed to isolate CSCs of Non-CSCs from cell lines. The Wound Healing assay was performed to confirm the presence of CSCs. After, the CSCs subpopulation and Non-CSCs were cultured and exposed for 24 h to Cetuximab and Paclitaxel treatment, separately. Cell proliferation was determined by MTS assay. CD44 and EGFR gene expression was quantified by quantitative real time PCR (qPCR) using TaqMan® Assay in both subpopulations. CSCs subpopulation untreated were considered as relative expression control. We firstly characterized CSCs in HN13 and HEP-2 cell lines with CD44, CD133 and CD117 biomarkers. We treated CSCs and Non-CSCs subpopulations with Cetuximab and Paclitaxel treatment and found that CSCs subpopulations demonstrated more resistance to Paclitaxel chemoterapy, when compared with Non-CSCs subpopulations of oral cancer cell line. These CSCs subpopulations presented up-regulation of CD44 gene and down-regulation of EGFR gene in oral cancer cell line, and down-regulation of CD44 gene and up-regulation of EGFR gene in laryngeal cancer cell line when compared with Non-CSCs subpopulations. We conclude that the combination of CD44, CD133 and CD117 biomarkers have stem cell properties in both cell lines. CSCs has ability to resist to Paclitaxel treatment in oral cancer cell line. CSCs present high expression of CD44 gene and down expression of EGFR gene in oral cancer cell line. CSCs in laryngeal cell line present down expression of CD44 gene and high expression of EGFR gene when compared with cells without characteristics of cancer stem cells.

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Novel Effector Phenotype of Tim-3+ Regulatory T Cells Leads to Enhanced Suppressive Function in Head and Neck Cancer Patients.

Publications

Novel Effector Phenotype of Tim-3<sup>+</sup> Regulatory T Cells Leads to Enhanced Suppressive Function in Head and Neck Cancer Patients.

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