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Cancer Discovery

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Targeting DNA Damage Response Promotes Antitumor Immunity through STING-Mediated T-cell Activation in Small Cell Lung Cancer

Triparna Sen, B. Leticia Rodriguez, Limo Chen, Carminia M. Della Corte, Naoto Morikawa, Junya Fujimoto, Sandra Cristea, Thuyen Nguyen, Lixia Diao, Lerong Li, Youhong Fan, Yongbin Yang, Jing Wang, Bonnie S. Glisson, Ignacio I. Wistuba, Julien Sage, John V. Heymach, Don L. Gibbons and Lauren A. Byers
Triparna Sen
Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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B. Leticia Rodriguez
Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Limo Chen
Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Carminia M. Della Corte
Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Naoto Morikawa
Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Junya Fujimoto
Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Sandra Cristea
Department of Pediatrics, Stanford University, Stanford, California.Department of Genetics, Stanford University, Stanford, California.
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Thuyen Nguyen
Department of Pediatrics, Stanford University, Stanford, California.Department of Genetics, Stanford University, Stanford, California.
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Lixia Diao
Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Lerong Li
Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Youhong Fan
Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Yongbin Yang
Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Jing Wang
Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Bonnie S. Glisson
Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Ignacio I. Wistuba
Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Julien Sage
Department of Pediatrics, Stanford University, Stanford, California.Department of Genetics, Stanford University, Stanford, California.
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  • ORCID record for Julien Sage
John V. Heymach
Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Don L. Gibbons
Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Lauren A. Byers
Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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  • For correspondence: lbyers@mdanderson.org
DOI: 10.1158/2159-8290.CD-18-1020 Published May 2019
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Abstract

Despite recent advances in the use of immunotherapy, only a minority of patients with small cell lung cancer (SCLC) respond to immune checkpoint blockade (ICB). Here, we show that targeting the DNA damage response (DDR) proteins PARP and checkpoint kinase 1 (CHK1) significantly increased protein and surface expression of PD-L1. PARP or CHK1 inhibition remarkably potentiated the antitumor effect of PD-L1 blockade and augmented cytotoxic T-cell infiltration in multiple immunocompetent SCLC in vivo models. CD8+ T-cell depletion reversed the antitumor effect, demonstrating the role of CD8+ T cells in combined DDR–PD-L1 blockade in SCLC. We further demonstrate that DDR inhibition activated the STING/TBK1/IRF3 innate immune pathway, leading to increased levels of chemokines such as CXCL10 and CCL5 that induced activation and function of cytotoxic T lymphocytes. Knockdown of cGAS and STING successfully reversed the antitumor effect of combined inhibition of DDR and PD-L1. Our results define previously unrecognized innate immune pathway–mediated immunomodulatory functions of DDR proteins and provide a rationale for combining PARP/CHK1 inhibitors and immunotherapies in SCLC.

Significance: Our results define previously unrecognized immunomodulatory functions of DDR inhibitors and suggest that adding PARP or CHK1 inhibitors to ICB may enhance treatment efficacy in patients with SCLC. Furthermore, our study supports a role of innate immune STING pathway in DDR-mediated antitumor immunity in SCLC.

See related commentary by Hiatt and MacPherson, p. 584.

This article is highlighted in the In This Issue feature, p. 565

Footnotes

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

  • Received September 4, 2018.
  • Revision received January 14, 2019.
  • Accepted January 30, 2019.
  • Published first February 18, 2019.
  • ©2019 American Association for Cancer Research.
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Cancer Discovery: 9 (5)
May 2019
Volume 9, Issue 5
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Targeting DNA Damage Response Promotes Antitumor Immunity through STING-Mediated T-cell Activation in Small Cell Lung Cancer
Triparna Sen, B. Leticia Rodriguez, Limo Chen, Carminia M. Della Corte, Naoto Morikawa, Junya Fujimoto, Sandra Cristea, Thuyen Nguyen, Lixia Diao, Lerong Li, Youhong Fan, Yongbin Yang, Jing Wang, Bonnie S. Glisson, Ignacio I. Wistuba, Julien Sage, John V. Heymach, Don L. Gibbons and Lauren A. Byers
Cancer Discov May 1 2019 (9) (5) 646-661; DOI: 10.1158/2159-8290.CD-18-1020

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Targeting DNA Damage Response Promotes Antitumor Immunity through STING-Mediated T-cell Activation in Small Cell Lung Cancer
Triparna Sen, B. Leticia Rodriguez, Limo Chen, Carminia M. Della Corte, Naoto Morikawa, Junya Fujimoto, Sandra Cristea, Thuyen Nguyen, Lixia Diao, Lerong Li, Youhong Fan, Yongbin Yang, Jing Wang, Bonnie S. Glisson, Ignacio I. Wistuba, Julien Sage, John V. Heymach, Don L. Gibbons and Lauren A. Byers
Cancer Discov May 1 2019 (9) (5) 646-661; DOI: 10.1158/2159-8290.CD-18-1020
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