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ResearchIn-Press PreviewCell biologyImmunologyOncology Open Access | 10.1172/JCI185423

NOTCH1 reverses immune suppression in small cell lung cancer through reactivation of STING

Yoo Sun Kim,1 Barzin Y. Nabet,2 Briana N. Cortez,1 Nai-Yun Sun,1 Robin Sebastian,1 Christophe E. Redon,1 Anagh Ray,1 Liang Liu,1 Afeez A. Ishola,1 Sarah Loew,1 Anjali Dhall,1 Sivasish Sindiri,3 Velimir Gayevskiy,2 Min-Jung Lee,1 Shraddha Rastogi,1 Nahoko Sato,1 Noemi Kedei,4 Thorkell Andresson,5 Sudipto Das,5 Suresh Kumar,1 Alan E. Bers,1 Hongliang Zhang,1 Alberto Chiappori,6 Priyanka Gopal,7 Mohamed E. Abazeed,7 Haobin Chen,8 Mirit I. Aladjem,1 Yves Pommier,1 Moises J. Velez,9 David S. Shames,2 and Nitin Roper1

1Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

2Genentech Inc., South San Francisco, United States of America

3Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

4Collaborative Protein Technology Resource, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

5Protein Characterization Laboratory, National Cancer Institute, Bethesda, United States of America

6Thoracic Oncology Program, Moffitt Cancer Center, Tampa, United States of America

7Department of Radiation Oncology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

8Division of Oncology, Department of Medicine, Washington University in St. Louis, St. Louis, United States of America

9Department of Pathology and Laboratory Medicine, University of Rochester, Rochester, United States of America

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1Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

2Genentech Inc., South San Francisco, United States of America

3Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

4Collaborative Protein Technology Resource, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

5Protein Characterization Laboratory, National Cancer Institute, Bethesda, United States of America

6Thoracic Oncology Program, Moffitt Cancer Center, Tampa, United States of America

7Department of Radiation Oncology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

8Division of Oncology, Department of Medicine, Washington University in St. Louis, St. Louis, United States of America

9Department of Pathology and Laboratory Medicine, University of Rochester, Rochester, United States of America

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1Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

2Genentech Inc., South San Francisco, United States of America

3Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

4Collaborative Protein Technology Resource, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

5Protein Characterization Laboratory, National Cancer Institute, Bethesda, United States of America

6Thoracic Oncology Program, Moffitt Cancer Center, Tampa, United States of America

7Department of Radiation Oncology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

8Division of Oncology, Department of Medicine, Washington University in St. Louis, St. Louis, United States of America

9Department of Pathology and Laboratory Medicine, University of Rochester, Rochester, United States of America

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1Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

2Genentech Inc., South San Francisco, United States of America

3Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

4Collaborative Protein Technology Resource, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

5Protein Characterization Laboratory, National Cancer Institute, Bethesda, United States of America

6Thoracic Oncology Program, Moffitt Cancer Center, Tampa, United States of America

7Department of Radiation Oncology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

8Division of Oncology, Department of Medicine, Washington University in St. Louis, St. Louis, United States of America

9Department of Pathology and Laboratory Medicine, University of Rochester, Rochester, United States of America

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1Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

2Genentech Inc., South San Francisco, United States of America

3Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

4Collaborative Protein Technology Resource, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

5Protein Characterization Laboratory, National Cancer Institute, Bethesda, United States of America

6Thoracic Oncology Program, Moffitt Cancer Center, Tampa, United States of America

7Department of Radiation Oncology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

8Division of Oncology, Department of Medicine, Washington University in St. Louis, St. Louis, United States of America

9Department of Pathology and Laboratory Medicine, University of Rochester, Rochester, United States of America

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1Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

2Genentech Inc., South San Francisco, United States of America

3Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

4Collaborative Protein Technology Resource, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

5Protein Characterization Laboratory, National Cancer Institute, Bethesda, United States of America

6Thoracic Oncology Program, Moffitt Cancer Center, Tampa, United States of America

7Department of Radiation Oncology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

8Division of Oncology, Department of Medicine, Washington University in St. Louis, St. Louis, United States of America

9Department of Pathology and Laboratory Medicine, University of Rochester, Rochester, United States of America

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1Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

2Genentech Inc., South San Francisco, United States of America

3Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

4Collaborative Protein Technology Resource, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

5Protein Characterization Laboratory, National Cancer Institute, Bethesda, United States of America

6Thoracic Oncology Program, Moffitt Cancer Center, Tampa, United States of America

7Department of Radiation Oncology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

8Division of Oncology, Department of Medicine, Washington University in St. Louis, St. Louis, United States of America

9Department of Pathology and Laboratory Medicine, University of Rochester, Rochester, United States of America

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1Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

2Genentech Inc., South San Francisco, United States of America

3Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

4Collaborative Protein Technology Resource, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

5Protein Characterization Laboratory, National Cancer Institute, Bethesda, United States of America

6Thoracic Oncology Program, Moffitt Cancer Center, Tampa, United States of America

7Department of Radiation Oncology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

8Division of Oncology, Department of Medicine, Washington University in St. Louis, St. Louis, United States of America

9Department of Pathology and Laboratory Medicine, University of Rochester, Rochester, United States of America

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1Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

2Genentech Inc., South San Francisco, United States of America

3Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

4Collaborative Protein Technology Resource, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

5Protein Characterization Laboratory, National Cancer Institute, Bethesda, United States of America

6Thoracic Oncology Program, Moffitt Cancer Center, Tampa, United States of America

7Department of Radiation Oncology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

8Division of Oncology, Department of Medicine, Washington University in St. Louis, St. Louis, United States of America

9Department of Pathology and Laboratory Medicine, University of Rochester, Rochester, United States of America

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1Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

2Genentech Inc., South San Francisco, United States of America

3Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

4Collaborative Protein Technology Resource, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

5Protein Characterization Laboratory, National Cancer Institute, Bethesda, United States of America

6Thoracic Oncology Program, Moffitt Cancer Center, Tampa, United States of America

7Department of Radiation Oncology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

8Division of Oncology, Department of Medicine, Washington University in St. Louis, St. Louis, United States of America

9Department of Pathology and Laboratory Medicine, University of Rochester, Rochester, United States of America

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1Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

2Genentech Inc., South San Francisco, United States of America

3Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

4Collaborative Protein Technology Resource, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

5Protein Characterization Laboratory, National Cancer Institute, Bethesda, United States of America

6Thoracic Oncology Program, Moffitt Cancer Center, Tampa, United States of America

7Department of Radiation Oncology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

8Division of Oncology, Department of Medicine, Washington University in St. Louis, St. Louis, United States of America

9Department of Pathology and Laboratory Medicine, University of Rochester, Rochester, United States of America

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1Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

2Genentech Inc., South San Francisco, United States of America

3Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

4Collaborative Protein Technology Resource, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

5Protein Characterization Laboratory, National Cancer Institute, Bethesda, United States of America

6Thoracic Oncology Program, Moffitt Cancer Center, Tampa, United States of America

7Department of Radiation Oncology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

8Division of Oncology, Department of Medicine, Washington University in St. Louis, St. Louis, United States of America

9Department of Pathology and Laboratory Medicine, University of Rochester, Rochester, United States of America

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1Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

2Genentech Inc., South San Francisco, United States of America

3Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

4Collaborative Protein Technology Resource, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

5Protein Characterization Laboratory, National Cancer Institute, Bethesda, United States of America

6Thoracic Oncology Program, Moffitt Cancer Center, Tampa, United States of America

7Department of Radiation Oncology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

8Division of Oncology, Department of Medicine, Washington University in St. Louis, St. Louis, United States of America

9Department of Pathology and Laboratory Medicine, University of Rochester, Rochester, United States of America

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1Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

2Genentech Inc., South San Francisco, United States of America

3Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

4Collaborative Protein Technology Resource, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

5Protein Characterization Laboratory, National Cancer Institute, Bethesda, United States of America

6Thoracic Oncology Program, Moffitt Cancer Center, Tampa, United States of America

7Department of Radiation Oncology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

8Division of Oncology, Department of Medicine, Washington University in St. Louis, St. Louis, United States of America

9Department of Pathology and Laboratory Medicine, University of Rochester, Rochester, United States of America

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1Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

2Genentech Inc., South San Francisco, United States of America

3Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

4Collaborative Protein Technology Resource, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

5Protein Characterization Laboratory, National Cancer Institute, Bethesda, United States of America

6Thoracic Oncology Program, Moffitt Cancer Center, Tampa, United States of America

7Department of Radiation Oncology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

8Division of Oncology, Department of Medicine, Washington University in St. Louis, St. Louis, United States of America

9Department of Pathology and Laboratory Medicine, University of Rochester, Rochester, United States of America

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1Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

2Genentech Inc., South San Francisco, United States of America

3Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

4Collaborative Protein Technology Resource, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

5Protein Characterization Laboratory, National Cancer Institute, Bethesda, United States of America

6Thoracic Oncology Program, Moffitt Cancer Center, Tampa, United States of America

7Department of Radiation Oncology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

8Division of Oncology, Department of Medicine, Washington University in St. Louis, St. Louis, United States of America

9Department of Pathology and Laboratory Medicine, University of Rochester, Rochester, United States of America

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1Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

2Genentech Inc., South San Francisco, United States of America

3Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

4Collaborative Protein Technology Resource, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

5Protein Characterization Laboratory, National Cancer Institute, Bethesda, United States of America

6Thoracic Oncology Program, Moffitt Cancer Center, Tampa, United States of America

7Department of Radiation Oncology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

8Division of Oncology, Department of Medicine, Washington University in St. Louis, St. Louis, United States of America

9Department of Pathology and Laboratory Medicine, University of Rochester, Rochester, United States of America

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1Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

2Genentech Inc., South San Francisco, United States of America

3Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

4Collaborative Protein Technology Resource, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

5Protein Characterization Laboratory, National Cancer Institute, Bethesda, United States of America

6Thoracic Oncology Program, Moffitt Cancer Center, Tampa, United States of America

7Department of Radiation Oncology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

8Division of Oncology, Department of Medicine, Washington University in St. Louis, St. Louis, United States of America

9Department of Pathology and Laboratory Medicine, University of Rochester, Rochester, United States of America

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1Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

2Genentech Inc., South San Francisco, United States of America

3Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

4Collaborative Protein Technology Resource, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

5Protein Characterization Laboratory, National Cancer Institute, Bethesda, United States of America

6Thoracic Oncology Program, Moffitt Cancer Center, Tampa, United States of America

7Department of Radiation Oncology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

8Division of Oncology, Department of Medicine, Washington University in St. Louis, St. Louis, United States of America

9Department of Pathology and Laboratory Medicine, University of Rochester, Rochester, United States of America

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1Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

2Genentech Inc., South San Francisco, United States of America

3Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

4Collaborative Protein Technology Resource, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

5Protein Characterization Laboratory, National Cancer Institute, Bethesda, United States of America

6Thoracic Oncology Program, Moffitt Cancer Center, Tampa, United States of America

7Department of Radiation Oncology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

8Division of Oncology, Department of Medicine, Washington University in St. Louis, St. Louis, United States of America

9Department of Pathology and Laboratory Medicine, University of Rochester, Rochester, United States of America

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1Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

2Genentech Inc., South San Francisco, United States of America

3Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

4Collaborative Protein Technology Resource, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

5Protein Characterization Laboratory, National Cancer Institute, Bethesda, United States of America

6Thoracic Oncology Program, Moffitt Cancer Center, Tampa, United States of America

7Department of Radiation Oncology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

8Division of Oncology, Department of Medicine, Washington University in St. Louis, St. Louis, United States of America

9Department of Pathology and Laboratory Medicine, University of Rochester, Rochester, United States of America

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1Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

2Genentech Inc., South San Francisco, United States of America

3Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

4Collaborative Protein Technology Resource, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

5Protein Characterization Laboratory, National Cancer Institute, Bethesda, United States of America

6Thoracic Oncology Program, Moffitt Cancer Center, Tampa, United States of America

7Department of Radiation Oncology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

8Division of Oncology, Department of Medicine, Washington University in St. Louis, St. Louis, United States of America

9Department of Pathology and Laboratory Medicine, University of Rochester, Rochester, United States of America

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1Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

2Genentech Inc., South San Francisco, United States of America

3Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

4Collaborative Protein Technology Resource, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

5Protein Characterization Laboratory, National Cancer Institute, Bethesda, United States of America

6Thoracic Oncology Program, Moffitt Cancer Center, Tampa, United States of America

7Department of Radiation Oncology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

8Division of Oncology, Department of Medicine, Washington University in St. Louis, St. Louis, United States of America

9Department of Pathology and Laboratory Medicine, University of Rochester, Rochester, United States of America

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1Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

2Genentech Inc., South San Francisco, United States of America

3Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

4Collaborative Protein Technology Resource, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

5Protein Characterization Laboratory, National Cancer Institute, Bethesda, United States of America

6Thoracic Oncology Program, Moffitt Cancer Center, Tampa, United States of America

7Department of Radiation Oncology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

8Division of Oncology, Department of Medicine, Washington University in St. Louis, St. Louis, United States of America

9Department of Pathology and Laboratory Medicine, University of Rochester, Rochester, United States of America

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1Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

2Genentech Inc., South San Francisco, United States of America

3Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

4Collaborative Protein Technology Resource, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

5Protein Characterization Laboratory, National Cancer Institute, Bethesda, United States of America

6Thoracic Oncology Program, Moffitt Cancer Center, Tampa, United States of America

7Department of Radiation Oncology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

8Division of Oncology, Department of Medicine, Washington University in St. Louis, St. Louis, United States of America

9Department of Pathology and Laboratory Medicine, University of Rochester, Rochester, United States of America

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1Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

2Genentech Inc., South San Francisco, United States of America

3Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

4Collaborative Protein Technology Resource, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

5Protein Characterization Laboratory, National Cancer Institute, Bethesda, United States of America

6Thoracic Oncology Program, Moffitt Cancer Center, Tampa, United States of America

7Department of Radiation Oncology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

8Division of Oncology, Department of Medicine, Washington University in St. Louis, St. Louis, United States of America

9Department of Pathology and Laboratory Medicine, University of Rochester, Rochester, United States of America

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1Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

2Genentech Inc., South San Francisco, United States of America

3Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

4Collaborative Protein Technology Resource, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

5Protein Characterization Laboratory, National Cancer Institute, Bethesda, United States of America

6Thoracic Oncology Program, Moffitt Cancer Center, Tampa, United States of America

7Department of Radiation Oncology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

8Division of Oncology, Department of Medicine, Washington University in St. Louis, St. Louis, United States of America

9Department of Pathology and Laboratory Medicine, University of Rochester, Rochester, United States of America

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1Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

2Genentech Inc., South San Francisco, United States of America

3Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

4Collaborative Protein Technology Resource, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

5Protein Characterization Laboratory, National Cancer Institute, Bethesda, United States of America

6Thoracic Oncology Program, Moffitt Cancer Center, Tampa, United States of America

7Department of Radiation Oncology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

8Division of Oncology, Department of Medicine, Washington University in St. Louis, St. Louis, United States of America

9Department of Pathology and Laboratory Medicine, University of Rochester, Rochester, United States of America

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1Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

2Genentech Inc., South San Francisco, United States of America

3Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

4Collaborative Protein Technology Resource, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

5Protein Characterization Laboratory, National Cancer Institute, Bethesda, United States of America

6Thoracic Oncology Program, Moffitt Cancer Center, Tampa, United States of America

7Department of Radiation Oncology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

8Division of Oncology, Department of Medicine, Washington University in St. Louis, St. Louis, United States of America

9Department of Pathology and Laboratory Medicine, University of Rochester, Rochester, United States of America

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1Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

2Genentech Inc., South San Francisco, United States of America

3Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

4Collaborative Protein Technology Resource, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

5Protein Characterization Laboratory, National Cancer Institute, Bethesda, United States of America

6Thoracic Oncology Program, Moffitt Cancer Center, Tampa, United States of America

7Department of Radiation Oncology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

8Division of Oncology, Department of Medicine, Washington University in St. Louis, St. Louis, United States of America

9Department of Pathology and Laboratory Medicine, University of Rochester, Rochester, United States of America

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1Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

2Genentech Inc., South San Francisco, United States of America

3Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

4Collaborative Protein Technology Resource, Center for Cancer Research, National Cancer Institute, Bethesda, United States of America

5Protein Characterization Laboratory, National Cancer Institute, Bethesda, United States of America

6Thoracic Oncology Program, Moffitt Cancer Center, Tampa, United States of America

7Department of Radiation Oncology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

8Division of Oncology, Department of Medicine, Washington University in St. Louis, St. Louis, United States of America

9Department of Pathology and Laboratory Medicine, University of Rochester, Rochester, United States of America

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Published July 8, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI185423.
Copyright © 2025, Kim et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published July 8, 2025 - Version history
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Abstract

Downregulation of antigen presentation and lack of immune infiltration are defining features of small cell lung cancer (SCLC) limiting response to immune checkpoint blockade (ICB). While a high MHC Class I, immune-inflamed subset benefits from ICB, underlying mechanisms of immune response in SCLC have yet to be elucidated. Here we show that in the landmark IMpower133 clinical trial high, but not low, NOTCH1 expression is significantly associated with longer survival with the addition of ICB to chemotherapy among ~80% of SCLC patients with neuroendocrine-enriched tumors (ASCL1-enriched, HR 0.39, P = 0.0012; NEUROD1-enriched, HR 0.44, P = 0.024). Overexpression or pharmacologic activation of NOTCH1 in ASCL1 and NEUROD1 SCLC cell lines dramatically upregulates MHC Class I through epigenetic reactivation of STING. In syngeneic mouse models, Notch1 activation reprograms SCLC tumors from immune-excluded to immune-inflamed, facilitating durable, complete responses with ICB combined with a STING agonist. STING1 expression is significantly enriched in high compared to low NOTCH1 expressing tumors in IMpower133 thereby validating our proposed mechanism. Our data reveal a previously undiscovered role for NOTCH1 as a critical driver of SCLC immunogenicity and a potential predictive biomarker for ICB in SCLC. NOTCH1 activation may be a therapeutic strategy to unleash anti-tumor immune responses in SCLC and other neuroendocrine cancers in which NOTCH1 is typically suppressed.

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