CAR T therapy targeting solid tumors is restrained by limited infiltration and persistence of those cells in the tumor microenvironment (TME). Here, we developed approaches to enhance the activity of CAR T cells using an orthotopic model of locally advanced breast cancer. CAR T cells generated from Th/Tc17 cells given with the STING agonists DMXAA or cGAMP greatly enhanced tumor control, which was associated with enhanced CAR T cell persistence in the TME. Using single-cell RNA sequencing, we demonstrate that DMXAA promoted CAR T cell trafficking and persistence, supported by the generation of a chemokine milieu that promoted CAR T cell recruitment and modulation of the immunosuppressive TME through alterations in the balance of immune-stimulatory and suppressive myeloid cells. However, sustained tumor regression was accomplished only with the addition of anti–PD-1 and anti–GR-1 mAb to Th/Tc17 CAR T cell therapy given with STING agonists. This study provides new approaches to enhance adoptive T cell therapy in solid tumors.
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December 31 2020
STING agonist promotes CAR T cell trafficking and persistence in breast cancer
Nuo Xu,
Nuo Xu
Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Resources, Validation, Visualization, Writing - original draft, Writing - review & editing
1
Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC
2
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC
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Douglas C. Palmer,
Douglas C. Palmer
Investigation, Methodology
3
Center for Cancer Research, National Cancer Institute, Bethesda, MD
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Alexander C. Robeson,
Alexander C. Robeson
Investigation, Methodology, Writing - review & editing
2
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC
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Peishun Shou,
Peishun Shou
Investigation, Resources, Writing - original draft
2
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC
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Hemamalini Bommiasamy,
Hemamalini Bommiasamy
Investigation, Project administration, Writing - review & editing
2
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC
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Sonia J. Laurie,
Sonia J. Laurie
Writing - original draft, Writing - review & editing
2
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC
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Caryn Willis,
Caryn Willis
Formal analysis
2
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC
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Gianpietro Dotti,
Gianpietro Dotti
Conceptualization, Supervision, Writing - review & editing
1
Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC
2
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC
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Benjamin G. Vincent,
Benjamin G. Vincent
Conceptualization, Formal analysis, Software, Writing - original draft, Writing - review & editing
1
Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC
2
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC
4
Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC
5
Curriculum in Bioinformatics and Computational Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC
6
Computational Medicine Program, University of North Carolina at Chapel Hill, Chapel Hill, NC
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Nicholas P. Restifo,
Nicholas P. Restifo
Conceptualization, Investigation, Methodology, Project administration, Supervision, Validation, Writing - original draft, Writing - review & editing
3
Center for Cancer Research, National Cancer Institute, Bethesda, MD
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Jonathan S. Serody
Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Writing - original draft, Writing - review & editing
1
Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC
2
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC
4
Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC
6
Computational Medicine Program, University of North Carolina at Chapel Hill, Chapel Hill, NC
Correspondence to Jonathan S. Serody: jonathan_serody@med.unc.edu
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Nuo Xu
Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Resources, Validation, Visualization, Writing - original draft, Writing - review & editing
1
Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC
2
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC
Douglas C. Palmer
Investigation, Methodology
3
Center for Cancer Research, National Cancer Institute, Bethesda, MD
Alexander C. Robeson
Investigation, Methodology, Writing - review & editing
2
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC
Peishun Shou
Investigation, Resources, Writing - original draft
2
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC
Hemamalini Bommiasamy
Investigation, Project administration, Writing - review & editing
2
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC
Sonia J. Laurie
Writing - original draft, Writing - review & editing
2
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC
Caryn Willis
Formal analysis
2
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC
Gianpietro Dotti
Conceptualization, Supervision, Writing - review & editing
1
Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC
2
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC
Benjamin G. Vincent
Conceptualization, Formal analysis, Software, Writing - original draft, Writing - review & editing
1
Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC
2
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC
4
Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC
5
Curriculum in Bioinformatics and Computational Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC
6
Computational Medicine Program, University of North Carolina at Chapel Hill, Chapel Hill, NC
Nicholas P. Restifo
Conceptualization, Investigation, Methodology, Project administration, Supervision, Validation, Writing - original draft, Writing - review & editing
3
Center for Cancer Research, National Cancer Institute, Bethesda, MD
Jonathan S. Serody
Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Writing - original draft, Writing - review & editing
1
Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC
2
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC
4
Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC
6
Computational Medicine Program, University of North Carolina at Chapel Hill, Chapel Hill, NC
Correspondence to Jonathan S. Serody: jonathan_serody@med.unc.edu
Received:
April 29 2020
Revision Received:
September 22 2020
Accepted:
November 12 2020
Online Issn: 1540-9538
Print Issn: 0022-1007
Funding:
National Cancer Institute
(P50 CA058223, CA16086)
© 2020 Xu et al.
2020
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
J Exp Med (2021) 218 (2): e20200844.
Article history
Received:
April 29 2020
Revision Received:
September 22 2020
Accepted:
November 12 2020
Citation
Nuo Xu, Douglas C. Palmer, Alexander C. Robeson, Peishun Shou, Hemamalini Bommiasamy, Sonia J. Laurie, Caryn Willis, Gianpietro Dotti, Benjamin G. Vincent, Nicholas P. Restifo, Jonathan S. Serody; STING agonist promotes CAR T cell trafficking and persistence in breast cancer. J Exp Med 1 February 2021; 218 (2): e20200844. doi: https://doi.org/10.1084/jem.20200844
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