IFN-γ Critically Enables the Intratumoural Infiltration of CXCR3<sup>+</sup> CD8<sup>+</sup> T Cells to Drive Squamous Cell Carcinoma Regression
Ultraviolet (UV) radiation-induced tumours carry a high mutational load, are highly immunogenic, and often fail to grow when transplanted into normal, syngeneic mice. The aim of this study was to investigate factors critical for the immune-mediated rejection of cutaneous squamous cell carcinoma (SCC...
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| Format: | Article |
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MDPI AG
2021-04-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/13/9/2131 |
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| author | Zhen Zeng Margaret Veitch Gabrielle A. Kelly Zewen K. Tuong Jazmina G. Cruz Ian H. Frazer James W. Wells |
| author_facet | Zhen Zeng Margaret Veitch Gabrielle A. Kelly Zewen K. Tuong Jazmina G. Cruz Ian H. Frazer James W. Wells |
| author_sort | Zhen Zeng |
| collection | DOAJ |
| description | Ultraviolet (UV) radiation-induced tumours carry a high mutational load, are highly immunogenic, and often fail to grow when transplanted into normal, syngeneic mice. The aim of this study was to investigate factors critical for the immune-mediated rejection of cutaneous squamous cell carcinoma (SCC). In our rejection model, transplanted SCC establish and grow in mice immunosuppressed with tacrolimus. When tacrolimus is withdrawn, established SCC tumours subsequently undergo immune-mediated tumour rejection. Through the depletion of individual immune subsets at the time of tacrolimus withdrawal, we established a critical role for CD8<sup>+</sup> T cells, but not CD4<sup>+</sup> T cells, γδ T cells, or NK cells, in driving the regression of SCC. Regression was critically dependent on IFN-γ, although IFN-γ was not directly cytotoxic to SCC cells. IFN-γ-neutralisation abrogated SCC regression, significantly reduced CD8<sup>+</sup> T cell-infiltration into SCC, and significantly impaired the secretion of CXCL9, CXCL10 and CCL5 within the tumour microenvironment. A strong positive correlation was revealed between CXCL10 expression and CD8<sup>+</sup> T cell abundance in tumours. Indeed, blockade of the CXCL10 receptor CXCR3 at the time of tacrolimus withdrawal prevented CD8<sup>+</sup> T cell infiltration and the regression of SCC. Chimeric models revealed an important role for immune cells as producers of IFN-γ, but not as recipients of IFN-γ signals via the IFN-γ receptor. Together, these findings suggest a key role for IFN-γ in driving the expression of chemokines within the tumour environment essential for the destruction of established SCC by CD8<sup>+</sup> T cells. |
| first_indexed | 2024-03-10T11:52:13Z |
| format | Article |
| id | doaj.art-840e94e4583d4a3ba2748af68557c14d |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T11:52:13Z |
| publishDate | 2021-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-840e94e4583d4a3ba2748af68557c14d2023-11-21T17:38:00ZengMDPI AGCancers2072-66942021-04-01139213110.3390/cancers13092131IFN-γ Critically Enables the Intratumoural Infiltration of CXCR3<sup>+</sup> CD8<sup>+</sup> T Cells to Drive Squamous Cell Carcinoma RegressionZhen Zeng0Margaret Veitch1Gabrielle A. Kelly2Zewen K. Tuong3Jazmina G. Cruz4Ian H. Frazer5James W. Wells6The University of Queensland Diamantina Institute, Faculty of Medicine, The University of Queensland, Brisbane, QLD 4102, AustraliaThe University of Queensland Diamantina Institute, Faculty of Medicine, The University of Queensland, Brisbane, QLD 4102, AustraliaThe University of Queensland Diamantina Institute, Faculty of Medicine, The University of Queensland, Brisbane, QLD 4102, AustraliaDepartment of Medicine, University of Cambridge, Cambridge CB2 0QH, UKThe University of Queensland Diamantina Institute, Faculty of Medicine, The University of Queensland, Brisbane, QLD 4102, AustraliaThe University of Queensland Diamantina Institute, Faculty of Medicine, The University of Queensland, Brisbane, QLD 4102, AustraliaThe University of Queensland Diamantina Institute, Faculty of Medicine, The University of Queensland, Brisbane, QLD 4102, AustraliaUltraviolet (UV) radiation-induced tumours carry a high mutational load, are highly immunogenic, and often fail to grow when transplanted into normal, syngeneic mice. The aim of this study was to investigate factors critical for the immune-mediated rejection of cutaneous squamous cell carcinoma (SCC). In our rejection model, transplanted SCC establish and grow in mice immunosuppressed with tacrolimus. When tacrolimus is withdrawn, established SCC tumours subsequently undergo immune-mediated tumour rejection. Through the depletion of individual immune subsets at the time of tacrolimus withdrawal, we established a critical role for CD8<sup>+</sup> T cells, but not CD4<sup>+</sup> T cells, γδ T cells, or NK cells, in driving the regression of SCC. Regression was critically dependent on IFN-γ, although IFN-γ was not directly cytotoxic to SCC cells. IFN-γ-neutralisation abrogated SCC regression, significantly reduced CD8<sup>+</sup> T cell-infiltration into SCC, and significantly impaired the secretion of CXCL9, CXCL10 and CCL5 within the tumour microenvironment. A strong positive correlation was revealed between CXCL10 expression and CD8<sup>+</sup> T cell abundance in tumours. Indeed, blockade of the CXCL10 receptor CXCR3 at the time of tacrolimus withdrawal prevented CD8<sup>+</sup> T cell infiltration and the regression of SCC. Chimeric models revealed an important role for immune cells as producers of IFN-γ, but not as recipients of IFN-γ signals via the IFN-γ receptor. Together, these findings suggest a key role for IFN-γ in driving the expression of chemokines within the tumour environment essential for the destruction of established SCC by CD8<sup>+</sup> T cells.https://www.mdpi.com/2072-6694/13/9/2131squamous cell carcinomaIFN-γCD8 T cellregressionimmune control |
| spellingShingle | Zhen Zeng Margaret Veitch Gabrielle A. Kelly Zewen K. Tuong Jazmina G. Cruz Ian H. Frazer James W. Wells IFN-γ Critically Enables the Intratumoural Infiltration of CXCR3<sup>+</sup> CD8<sup>+</sup> T Cells to Drive Squamous Cell Carcinoma Regression Cancers squamous cell carcinoma IFN-γ CD8 T cell regression immune control |
| title | IFN-γ Critically Enables the Intratumoural Infiltration of CXCR3<sup>+</sup> CD8<sup>+</sup> T Cells to Drive Squamous Cell Carcinoma Regression |
| title_full | IFN-γ Critically Enables the Intratumoural Infiltration of CXCR3<sup>+</sup> CD8<sup>+</sup> T Cells to Drive Squamous Cell Carcinoma Regression |
| title_fullStr | IFN-γ Critically Enables the Intratumoural Infiltration of CXCR3<sup>+</sup> CD8<sup>+</sup> T Cells to Drive Squamous Cell Carcinoma Regression |
| title_full_unstemmed | IFN-γ Critically Enables the Intratumoural Infiltration of CXCR3<sup>+</sup> CD8<sup>+</sup> T Cells to Drive Squamous Cell Carcinoma Regression |
| title_short | IFN-γ Critically Enables the Intratumoural Infiltration of CXCR3<sup>+</sup> CD8<sup>+</sup> T Cells to Drive Squamous Cell Carcinoma Regression |
| title_sort | ifn γ critically enables the intratumoural infiltration of cxcr3 sup sup cd8 sup sup t cells to drive squamous cell carcinoma regression |
| topic | squamous cell carcinoma IFN-γ CD8 T cell regression immune control |
| url | https://www.mdpi.com/2072-6694/13/9/2131 |
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