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Cancer Immunology Research
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Stereotactic Radiotherapy Increases Functionally Suppressive Regulatory T Cells in the Tumor Microenvironment

Yuki Muroyama, Thomas R. Nirschl, Christina M. Kochel, Zoila Lopez-Bujanda, Debebe Theodros, Wendy Mao, Maria A. Carrera-Haro, Ali Ghasemzadeh, Ariel E. Marciscano, Esteban Velarde, Ada J. Tam, Christopher J. Thoburn, Muniza Uddin, Alan K. Meeker, Robert A. Anders, Drew M. Pardoll and Charles G. Drake
Yuki Muroyama
1Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
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Thomas R. Nirschl
1Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
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Christina M. Kochel
1Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
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Zoila Lopez-Bujanda
1Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
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Debebe Theodros
1Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
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Wendy Mao
1Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
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Maria A. Carrera-Haro
1Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
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Ali Ghasemzadeh
1Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
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Ariel E. Marciscano
2Department of Radiation Oncology and Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
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Esteban Velarde
2Department of Radiation Oncology and Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
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Ada J. Tam
1Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
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Christopher J. Thoburn
1Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
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Muniza Uddin
3Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
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Alan K. Meeker
3Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
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Robert A. Anders
3Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
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Drew M. Pardoll
1Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
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Charles G. Drake
1Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
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  • For correspondence: cgd2139@cumc.columbia.edu
DOI: 10.1158/2326-6066.CIR-17-0040 Published November 2017
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Abstract

Radiotherapy (RT) enhances innate and adaptive antitumor immunity; however, the effects of radiation on suppressive immune cells, such as regulatory T cells (Treg), in the tumor microenvironment (TME) are not fully elucidated. Although previous reports suggest an increased Treg infiltration after radiation, whether these Tregs are functionally suppressive remains undetermined. To test the hypothesis that RT enhances the suppressive function of Treg in the TME, we selectively irradiated implanted tumors using the small animal radiation research platform (SARRP), which models stereotactic radiotherapy in human patients. We then analyzed tumor-infiltrating lymphocytes (TIL) with flow-cytometry and functional assays. Our data showed that RT significantly increased tumor-infiltrating Tregs (TIL-Treg), which had higher expression of CTLA-4, 4-1BB, and Helios compared with Tregs in nonirradiated tumors. This observation held true across several tumor models (B16/F10, RENCA, and MC38). We found that TIL-Tregs from irradiated tumors had equal or improved suppressive capacity compared with nonirradiated tumors. Our data also indicated that after RT, Tregs proliferated more robustly than other T-cell subsets in the TME. In addition, after RT, expansion of Tregs occurred when T-cell migration was inhibited using Fingolimod, suggesting that the increased Treg frequency was likely due to preferential proliferation of intratumoral Treg after radiation. Our data also suggested that Treg expansion after irradiation was independent of TGFβ and IL33 signaling. These data demonstrate that RT increased phenotypically and functionally suppressive Tregs in the TME. Our results suggest that RT might be combined effectively with Treg-targeting agents to maximize antitumor efficacy. Cancer Immunol Res; 5(11); 992–1004. ©2017 AACR.

Footnotes

  • Note: Supplementary data for this article are available at Cancer Immunology Research Online (http://cancerimmunolres.aacrjournals.org/).

  • Received January 21, 2017.
  • Revision received June 12, 2017.
  • Accepted September 26, 2017.
  • ©2017 American Association for Cancer Research.
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Cancer Immunology Research: 5 (11)
November 2017
Volume 5, Issue 11
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Stereotactic Radiotherapy Increases Functionally Suppressive Regulatory T Cells in the Tumor Microenvironment
Yuki Muroyama, Thomas R. Nirschl, Christina M. Kochel, Zoila Lopez-Bujanda, Debebe Theodros, Wendy Mao, Maria A. Carrera-Haro, Ali Ghasemzadeh, Ariel E. Marciscano, Esteban Velarde, Ada J. Tam, Christopher J. Thoburn, Muniza Uddin, Alan K. Meeker, Robert A. Anders, Drew M. Pardoll and Charles G. Drake
Cancer Immunol Res November 1 2017 (5) (11) 992-1004; DOI: 10.1158/2326-6066.CIR-17-0040

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Stereotactic Radiotherapy Increases Functionally Suppressive Regulatory T Cells in the Tumor Microenvironment
Yuki Muroyama, Thomas R. Nirschl, Christina M. Kochel, Zoila Lopez-Bujanda, Debebe Theodros, Wendy Mao, Maria A. Carrera-Haro, Ali Ghasemzadeh, Ariel E. Marciscano, Esteban Velarde, Ada J. Tam, Christopher J. Thoburn, Muniza Uddin, Alan K. Meeker, Robert A. Anders, Drew M. Pardoll and Charles G. Drake
Cancer Immunol Res November 1 2017 (5) (11) 992-1004; DOI: 10.1158/2326-6066.CIR-17-0040
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