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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Project description:PurposeTo identify which patient-reported outcomes (PROs) may be most improved through adaptive radiation therapy (ART) with the goal of reducing toxicity incidence among head and neck cancer patients.MethodsOne hundred fifty-five head and neck cancer patients receiving radical VMAT (chemo)radiotherapy (66-70 Gy in 30-35 fractions) completed the MD Anderson Symptom Inventory, MD Anderson Dysphagia Inventory (MDADI), and Xerostomia Questionnaire while attending routine follow-up clinics between June-October 2019. Hierarchical clustering characterized symptom endorsement. Conventional statistical approaches indicated associations between dose and commonly reported symptoms. These associations, and the potential benefit of interfractional dose corrections, were further explored via logistic regression.ResultsRadiotherapy-related symptoms were commonly reported (dry mouth, difficulty swallowing/chewing). Clustering identified three patient subgroups reporting: none/mild symptoms for most items (60.6% of patients); moderate/severe symptoms affecting some aspects of general well-being (32.9%); and moderate/severe symptom reporting for most items (6.5%). Clusters of PRO items broadly consisted of acute toxicities, general well-being, and head and neck-specific symptoms (xerostomia, dysphagia). Dose-PRO relationships were strongest between delivered pharyngeal constrictor Dmean and patient-reported dysphagia, with MDADI composite scores (mean ± SD) of 25.7 ± 18.9 for patients with Dmean <50 Gy vs. 32.4 ± 17.1 with Dmean ≥50 Gy. Based on logistic regression models, during-treatment dose corrections back to planned values may confer ≥5% decrease in the absolute risk of self-reported physical dysphagia symptoms ≥1 year post-treatment in 1.2% of patients, with a ≥5% decrease in relative risk in 23.3% of patients.ConclusionsPatient-reported dysphagia symptoms are strongly associated with delivered dose to the pharyngeal constrictor. Dysphagia-focused ART may provide the greatest toxicity benefit to head and neck cancer patients, and represent a potential new direction for ART, given that the existing ART literature has focused almost exclusively on xerostomia reduction.

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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