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Improving function of cytotoxic T-lymphocytes by transforming growth factor-β inhibitor in oral squamous cell carcinoma.
- Source :
-
Cancer science [Cancer Sci] 2021 Oct; Vol. 112 (10), pp. 4037-4049. Date of Electronic Publication: 2021 Aug 02. - Publication Year :
- 2021
-
Abstract
- Immunotherapy with immune-checkpoint therapy has recently been used to treat oral squamous cell carcinomas (OSCCs). However, improvements in current immunotherapy are expected because response rates are limited. Transforming growth factor-β (TGF-β) creates an immunosuppressive tumor microenvironment (TME) by inducing the production of regulatory T-cells (Tregs) and cancer-associated fibroblasts and inhibiting the function of cytotoxic T-lymphocytes (CTLs) and natural killer cells. TGF-β may be an important target in the development of novel cancer immunotherapies. In this study, we investigated the suppressive effect of TGF-β on CTL function in vitro using OSCC cell lines and their specific CTLs. Moreover, TGFB1 mRNA expression and T-cell infiltration in 25 OSCC tissues were examined by in situ hybridization and multifluorescence immunohistochemistry. We found that TGF-β suppressed the function of antigen-specific CTLs in the priming and effector phases in vitro. Additionally, TGF-β inhibitor effectively restored the CTL function, and TGFB1 mRNA was primarily expressed in the tumor invasive front. Interestingly, we found a significant negative correlation between TGFB1 mRNA expression and the CD8 <superscript>+</superscript> T-cell/Treg ratio and between TGFB1 mRNA expression and the Ki-67 expression in CD8 <superscript>+</superscript> T-cells, indicating that TGF-β also suppressed the function of CTLs in situ. Our findings suggest that the regulation of TGF-β function restores the immunosuppressive TME to active status and is important for developing new immunotherapeutic strategies, such as a combination of immune-checkpoint inhibitors and TGF-β inhibitors, for OSCCs.<br /> (© 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)
- Subjects :
- Adult
Aged
Aged, 80 and over
CD8-Positive T-Lymphocytes cytology
CD8-Positive T-Lymphocytes immunology
Cancer-Associated Fibroblasts cytology
Cancer-Associated Fibroblasts immunology
Cell Line, Tumor
Cell Proliferation
Female
Humans
Interferon-gamma analysis
Interferon-gamma metabolism
Ki-67 Antigen metabolism
Killer Cells, Natural cytology
Killer Cells, Natural immunology
Lymphocytes, Tumor-Infiltrating cytology
Lymphocytes, Tumor-Infiltrating immunology
Male
Middle Aged
Mouth Neoplasms metabolism
RNA, Messenger metabolism
Smad2 Protein metabolism
Smad3 Protein metabolism
Squamous Cell Carcinoma of Head and Neck metabolism
T-Lymphocytes, Cytotoxic cytology
T-Lymphocytes, Cytotoxic immunology
T-Lymphocytes, Cytotoxic metabolism
T-Lymphocytes, Regulatory cytology
T-Lymphocytes, Regulatory immunology
Tetrazolium Salts pharmacology
Transforming Growth Factor beta antagonists & inhibitors
Transforming Growth Factor beta immunology
Transforming Growth Factor beta1 analysis
Transforming Growth Factor beta1 genetics
Transforming Growth Factor beta1 metabolism
Tumor Necrosis Factor-alpha analysis
Tumor Necrosis Factor-alpha metabolism
Young Adult
Immune Checkpoint Inhibitors therapeutic use
Immunotherapy, Adoptive methods
Mouth Neoplasms therapy
Squamous Cell Carcinoma of Head and Neck therapy
T-Lymphocytes, Cytotoxic drug effects
Transforming Growth Factor beta1 antagonists & inhibitors
Tumor Microenvironment immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1349-7006
- Volume :
- 112
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Cancer science
- Publication Type :
- Academic Journal
- Accession number :
- 34309966
- Full Text :
- https://doi.org/10.1111/cas.15081