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ResearchIn-Press PreviewNeuroscienceOncology Open Access | 10.1172/JCI181471

IL-7-mediated expansion of autologous lymphocytes increases CD8+ VLA-4 expression and accumulation in glioblastoma models

Kirit Singh,1 Kelly M. Hotchkiss,1 Sarah L. Cook,1 Pamy Noldner,2 Ying Zhou,2 Eliese M. Moelker,1 Chelsea O. Railton,1 Emily E. Blandford,1 Bhairavy J. Puviindran,1 Shannon E. Wallace,1 Pamela K. Norberg,1 Gary E. Archer,1 Beth H. Shaz,2 Katayoun Ayasoufi,1 John H. Sampson,3 Mustafa Khasraw,1 and Peter E. Fecci1

1The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, United States of America

2The Marcus Center for Cellular Cures, Duke University Medical Center, Durham, United States of America

3Department of Neurosurgery, University of Colorado Anschutz Medical Campus, Aurora, United States of America

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1The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, United States of America

2The Marcus Center for Cellular Cures, Duke University Medical Center, Durham, United States of America

3Department of Neurosurgery, University of Colorado Anschutz Medical Campus, Aurora, United States of America

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1The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, United States of America

2The Marcus Center for Cellular Cures, Duke University Medical Center, Durham, United States of America

3Department of Neurosurgery, University of Colorado Anschutz Medical Campus, Aurora, United States of America

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1The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, United States of America

2The Marcus Center for Cellular Cures, Duke University Medical Center, Durham, United States of America

3Department of Neurosurgery, University of Colorado Anschutz Medical Campus, Aurora, United States of America

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1The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, United States of America

2The Marcus Center for Cellular Cures, Duke University Medical Center, Durham, United States of America

3Department of Neurosurgery, University of Colorado Anschutz Medical Campus, Aurora, United States of America

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1The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, United States of America

2The Marcus Center for Cellular Cures, Duke University Medical Center, Durham, United States of America

3Department of Neurosurgery, University of Colorado Anschutz Medical Campus, Aurora, United States of America

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1The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, United States of America

2The Marcus Center for Cellular Cures, Duke University Medical Center, Durham, United States of America

3Department of Neurosurgery, University of Colorado Anschutz Medical Campus, Aurora, United States of America

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1The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, United States of America

2The Marcus Center for Cellular Cures, Duke University Medical Center, Durham, United States of America

3Department of Neurosurgery, University of Colorado Anschutz Medical Campus, Aurora, United States of America

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1The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, United States of America

2The Marcus Center for Cellular Cures, Duke University Medical Center, Durham, United States of America

3Department of Neurosurgery, University of Colorado Anschutz Medical Campus, Aurora, United States of America

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1The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, United States of America

2The Marcus Center for Cellular Cures, Duke University Medical Center, Durham, United States of America

3Department of Neurosurgery, University of Colorado Anschutz Medical Campus, Aurora, United States of America

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1The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, United States of America

2The Marcus Center for Cellular Cures, Duke University Medical Center, Durham, United States of America

3Department of Neurosurgery, University of Colorado Anschutz Medical Campus, Aurora, United States of America

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1The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, United States of America

2The Marcus Center for Cellular Cures, Duke University Medical Center, Durham, United States of America

3Department of Neurosurgery, University of Colorado Anschutz Medical Campus, Aurora, United States of America

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1The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, United States of America

2The Marcus Center for Cellular Cures, Duke University Medical Center, Durham, United States of America

3Department of Neurosurgery, University of Colorado Anschutz Medical Campus, Aurora, United States of America

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1The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, United States of America

2The Marcus Center for Cellular Cures, Duke University Medical Center, Durham, United States of America

3Department of Neurosurgery, University of Colorado Anschutz Medical Campus, Aurora, United States of America

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1The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, United States of America

2The Marcus Center for Cellular Cures, Duke University Medical Center, Durham, United States of America

3Department of Neurosurgery, University of Colorado Anschutz Medical Campus, Aurora, United States of America

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1The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, United States of America

2The Marcus Center for Cellular Cures, Duke University Medical Center, Durham, United States of America

3Department of Neurosurgery, University of Colorado Anschutz Medical Campus, Aurora, United States of America

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1The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, United States of America

2The Marcus Center for Cellular Cures, Duke University Medical Center, Durham, United States of America

3Department of Neurosurgery, University of Colorado Anschutz Medical Campus, Aurora, United States of America

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Published April 17, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI181471.
Copyright © 2025, Singh 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 April 17, 2025 - Version history
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Abstract

The efficacy of T cell-activating therapies against glioma is limited by an immunosuppressive tumor microenvironment and tumor-induced T cell sequestration. We investigated whether peripherally infused non-antigen specific autologous lymphocytes (ALT) could accumulate in intracranial tumors. We observed that non-specific autologous CD8+ ALT cells can indeed accumulate in this context, despite endogenous T cell sequestration in bone marrow. Rates of intratumoral accumulation were markedly increased when expanding lymphocytes with IL-7 compared to IL-2. Pre-treatment with IL-7 ALT also enhanced the efficacy of multiple tumor-specific and non-tumor-specific T cell-dependent immunotherapies against orthotopic murine and human xenograft gliomas. Mechanistically, we detected increased VLA-4 on mouse and human CD8+ T cells following IL-7 expansion, with increased transcription of genes associated with migratory integrin expression (CD9). We also observed that IL-7 increases S1PR1 transcription in human CD8+ T cells, which we have shown to be protective against tumor-induced T cell sequestration. These observations demonstrate that expansion with IL-7 enhances the capacity of ALT to accumulate within intracranial tumors, and that pre-treatment with IL-7 ALT can boost the efficacy of subsequent T cell-activating therapies against glioma. Our findings will inform the development of future clinical trials where ALT pre-treatment can be combined with T cell-activating therapies.

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