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ResearchIn-Press PreviewCell biologyImmunologyOncology Open Access | 10.1172/JCI191070

Lung adenocarcinoma-derived IFN-γ promotes growth by modulating CD8+ T cell production of CCR5 chemokines

Christina Kratzmeier,1 Mojtaba Taheri,1 Zhongcheng Mei,1 Isabelle Lim,1 May A. Khalil,1 Brandon Carter-Cooper,2 Rachel E. Fanaroff,3 Chin S. Ong,4 Eric B. Schneider,4 Stephanie Chang,5 Erica Leyder,1 Dongge Li,1 Irina G. Luzina,6 Anirban Banerjee,1 and Alexander Sasha Krupnick1

1Department of Surgery, University of Maryland, Baltimore, United States of America

2University of Maryland, Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, United States of America

3Department of Anatomical Pathology, University of Maryland, Baltimore, United States of America

4Department of Surgery, Yale School of Medicine, New Haven, United States of America

5Department of Cardiothoracic Surgery, New York University, New York, United States of America

6Department of Medicine, University of Maryland, Baltimore, United States of America

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1Department of Surgery, University of Maryland, Baltimore, United States of America

2University of Maryland, Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, United States of America

3Department of Anatomical Pathology, University of Maryland, Baltimore, United States of America

4Department of Surgery, Yale School of Medicine, New Haven, United States of America

5Department of Cardiothoracic Surgery, New York University, New York, United States of America

6Department of Medicine, University of Maryland, Baltimore, United States of America

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1Department of Surgery, University of Maryland, Baltimore, United States of America

2University of Maryland, Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, United States of America

3Department of Anatomical Pathology, University of Maryland, Baltimore, United States of America

4Department of Surgery, Yale School of Medicine, New Haven, United States of America

5Department of Cardiothoracic Surgery, New York University, New York, United States of America

6Department of Medicine, University of Maryland, Baltimore, United States of America

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1Department of Surgery, University of Maryland, Baltimore, United States of America

2University of Maryland, Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, United States of America

3Department of Anatomical Pathology, University of Maryland, Baltimore, United States of America

4Department of Surgery, Yale School of Medicine, New Haven, United States of America

5Department of Cardiothoracic Surgery, New York University, New York, United States of America

6Department of Medicine, University of Maryland, Baltimore, United States of America

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1Department of Surgery, University of Maryland, Baltimore, United States of America

2University of Maryland, Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, United States of America

3Department of Anatomical Pathology, University of Maryland, Baltimore, United States of America

4Department of Surgery, Yale School of Medicine, New Haven, United States of America

5Department of Cardiothoracic Surgery, New York University, New York, United States of America

6Department of Medicine, University of Maryland, Baltimore, United States of America

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1Department of Surgery, University of Maryland, Baltimore, United States of America

2University of Maryland, Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, United States of America

3Department of Anatomical Pathology, University of Maryland, Baltimore, United States of America

4Department of Surgery, Yale School of Medicine, New Haven, United States of America

5Department of Cardiothoracic Surgery, New York University, New York, United States of America

6Department of Medicine, University of Maryland, Baltimore, United States of America

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1Department of Surgery, University of Maryland, Baltimore, United States of America

2University of Maryland, Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, United States of America

3Department of Anatomical Pathology, University of Maryland, Baltimore, United States of America

4Department of Surgery, Yale School of Medicine, New Haven, United States of America

5Department of Cardiothoracic Surgery, New York University, New York, United States of America

6Department of Medicine, University of Maryland, Baltimore, United States of America

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1Department of Surgery, University of Maryland, Baltimore, United States of America

2University of Maryland, Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, United States of America

3Department of Anatomical Pathology, University of Maryland, Baltimore, United States of America

4Department of Surgery, Yale School of Medicine, New Haven, United States of America

5Department of Cardiothoracic Surgery, New York University, New York, United States of America

6Department of Medicine, University of Maryland, Baltimore, United States of America

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1Department of Surgery, University of Maryland, Baltimore, United States of America

2University of Maryland, Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, United States of America

3Department of Anatomical Pathology, University of Maryland, Baltimore, United States of America

4Department of Surgery, Yale School of Medicine, New Haven, United States of America

5Department of Cardiothoracic Surgery, New York University, New York, United States of America

6Department of Medicine, University of Maryland, Baltimore, United States of America

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1Department of Surgery, University of Maryland, Baltimore, United States of America

2University of Maryland, Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, United States of America

3Department of Anatomical Pathology, University of Maryland, Baltimore, United States of America

4Department of Surgery, Yale School of Medicine, New Haven, United States of America

5Department of Cardiothoracic Surgery, New York University, New York, United States of America

6Department of Medicine, University of Maryland, Baltimore, United States of America

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1Department of Surgery, University of Maryland, Baltimore, United States of America

2University of Maryland, Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, United States of America

3Department of Anatomical Pathology, University of Maryland, Baltimore, United States of America

4Department of Surgery, Yale School of Medicine, New Haven, United States of America

5Department of Cardiothoracic Surgery, New York University, New York, United States of America

6Department of Medicine, University of Maryland, Baltimore, United States of America

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1Department of Surgery, University of Maryland, Baltimore, United States of America

2University of Maryland, Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, United States of America

3Department of Anatomical Pathology, University of Maryland, Baltimore, United States of America

4Department of Surgery, Yale School of Medicine, New Haven, United States of America

5Department of Cardiothoracic Surgery, New York University, New York, United States of America

6Department of Medicine, University of Maryland, Baltimore, United States of America

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1Department of Surgery, University of Maryland, Baltimore, United States of America

2University of Maryland, Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, United States of America

3Department of Anatomical Pathology, University of Maryland, Baltimore, United States of America

4Department of Surgery, Yale School of Medicine, New Haven, United States of America

5Department of Cardiothoracic Surgery, New York University, New York, United States of America

6Department of Medicine, University of Maryland, Baltimore, United States of America

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1Department of Surgery, University of Maryland, Baltimore, United States of America

2University of Maryland, Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, United States of America

3Department of Anatomical Pathology, University of Maryland, Baltimore, United States of America

4Department of Surgery, Yale School of Medicine, New Haven, United States of America

5Department of Cardiothoracic Surgery, New York University, New York, United States of America

6Department of Medicine, University of Maryland, Baltimore, United States of America

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1Department of Surgery, University of Maryland, Baltimore, United States of America

2University of Maryland, Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, United States of America

3Department of Anatomical Pathology, University of Maryland, Baltimore, United States of America

4Department of Surgery, Yale School of Medicine, New Haven, United States of America

5Department of Cardiothoracic Surgery, New York University, New York, United States of America

6Department of Medicine, University of Maryland, Baltimore, United States of America

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Published June 24, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI191070.
Copyright © 2025, Kratzmeier 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 June 24, 2025 - Version history
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Abstract

Since the lung is a mucosal barrier organ with a unique immunologic environment, mechanisms of immunoregulation in lung cancer may differ from those of other malignancies. Consistent with this notion, we found that CD8+ T cells play a paradoxical role in facilitating, rather than ameliorating, the growth of multiple lung adenocarcinoma models. These include spontaneous, carcinogen-induced, and transplantable tumor cell line models. Specifically, we found that CD8+ T cells promote homing of CD4+Foxp3+ T regulatory cells to the tumor bed by increasing levels of CCR5 chemokines in the tumor microenvironment in an IFN-γ and TNF-α dependent manner. Contrary to their canonical role, these Th1 cytokines contributed to accelerated growth of murine lung adenocarcinomas while suppressing the growth of other malignancies. Surprisingly, lung cancer cells themselves can serve as a dominant source of IFN-γ, and deletion of this cytokine from cancer cells using CRISPR/Cas-9 decreases tumor growth. Importantly for translational applications, a high level of IFN-γ was also found in human lung cancer patients at both the mRNA and protein level. Our data outlines what we deem a novel and previously undefined lung cancer specific immunoregulatory pathway that may be harnessed to tailor immune based therapy specifically for this malignancy.

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