Dataset Information

STAT3 Modulation of Regulatory T Cells in Response to Radiation Therapy in Head and Neck Cancer.

ABSTRACT:

Background

Radioresistance represents a major problem in the treatment of head and neck cancer (HNC) patients. To improve response, understanding tumor microenvironmental factors that contribute to radiation resistance is important. Regulatory T cells (Tregs) are enriched in numerous cancers and can dampen the response to radiation by creating an immune-inhibitory microenvironment. The purpose of this study was to investigate mechanisms of Treg modulation by radiation in HNC.

Methods

We utilized an orthotopic mouse model of HNC. Anti-CD25 was used for Treg depletion. Image-guided radiation was delivered to a dose of 10?Gy. Flow cytometry was used to analyze abundance and function of intratumoral immune cells. Enzyme-linked immunosorbent assay was performed to assess secreted factors. For immune-modulating therapies, anti-PD-L1, anti-CTLA-4, and STAT3 antisense oligonucleotide (ASO) were used. All statistical tests were two-sided.

Results

Treatment with anti-CD25 and radiation led to tumor eradication (57.1%, n?=?4 of 7 mice), enhanced T-cell cytotoxicity compared with RT alone (CD4 effector T cells [Teff]: RT group mean?=?5.37 [?0.58] vs RT?+??CD25 group mean =10.71 [0.67], P?=?.005; CD8 Teff: RT group mean?=?9.98 [0.81] vs RT?+??CD25 group mean =16.88 [2.49], P = .01) and induced tumor antigen-specific memory response (100.0%, n?=?4 mice). In contrast, radiation alone or when combined with anti-CTLA4 did not lead to durable tumor control (0.0%, n?=?7 mice). STAT3 inhibition in combination with radiation, but not as a single agent, improved tumor growth delay, decreased Tregs, myeloid-derived suppressor cells, and M2 macrophages and enhanced effector T cells and M1 macrophages. Experiments in nude mice inhibited the benefit of STAT3 ASO and radiation.

Conclusion

We propose that STAT3 inhibition is a viable and potent therapeutic target against Tregs. Our data support the design of clinical trials integrating STAT3 ASO in the standard of care for cancer patients receiving radiation.

SUBMITTER: Oweida AJ

PROVIDER: S-EPMC6910208 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Publications

STAT3 Modulation of Regulatory T Cells in Response to Radiation Therapy in Head and Neck Cancer.

Oweida Ayman J AJ Darragh Laurel L Phan Andy A Binder David D Bhatia Shilpa S Mueller Adam A Court Benjamin Van BV Milner Dallin D Raben David D Woessner Richard R Heasley Lynn L Nemenoff Raphael R Clambey Eric E Karam Sana D SD

Journal of the National Cancer Institute 20191201 12

<h4>Background</h4>Radioresistance represents a major problem in the treatment of head and neck cancer (HNC) patients. To improve response, understanding tumor microenvironmental factors that contribute to radiation resistance is important. Regulatory T cells (Tregs) are enriched in numerous cancers and can dampen the response to radiation by creating an immune-inhibitory microenvironment. The purpose of this study was to investigate mechanisms of Treg modulation by radiation in HNC.<h4>Methods< ...[more]

PMID: 30863843

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Dataset Information

STAT3 Modulation of Regulatory T Cells in Response to Radiation Therapy in Head and Neck Cancer.

Background

Methods

Results

Conclusion

Publications

STAT3 Modulation of Regulatory T Cells in Response to Radiation Therapy in Head and Neck Cancer.

Similar Datasets

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