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Intratumoral Activation of 41BB Costimulatory Signals Enhances CD8 T Cell Expansion and Modulates Tumor-Infiltrating Myeloid Cells

Patrick Innamarato, Sarah Asby, Jennifer Morse, Amy Mackay, MacLean Hall, Scott Kidd, Luz Nagle, Amod A. Sarnaik and Shari Pilon-Thomas
J Immunol October 5, 2020, ji2000759; DOI: https://doi.org/10.4049/jimmunol.2000759
Patrick Innamarato
*Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612;
†Cancer Biology Ph.D. Program, University of South Florida, Tampa, FL 33620; and
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Sarah Asby
*Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612;
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Jennifer Morse
*Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612;
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Amy Mackay
*Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612;
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MacLean Hall
*Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612;
†Cancer Biology Ph.D. Program, University of South Florida, Tampa, FL 33620; and
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Scott Kidd
*Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612;
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Luz Nagle
*Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612;
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Amod A. Sarnaik
*Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612;
‡Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center, Tampa, FL 33612
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Shari Pilon-Thomas
*Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612;
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Key Points

  • Intratumoral 41BB agonism induces tumor regression in mouse models.

  • 41BB agonism potentiates myeloid-mediated costimulation in tumors.

  • Activation of 41BBL but not 41BB in human APCs promotes costimulatory responses.

Abstract

The activation of 41BB costimulatory signals by agonistic Abs enhances the expansion and function of tumor-infiltrating lymphocytes (TILs) for treating cancer patients with adoptive cell therapy. However, the impact of 41BB agonism is not limited to enhancing the activity of T cells, and the mechanism by which additional activation of this costimulatory axis in tumor-associated myeloid cells is poorly understood. In this study, we describe that the intratumoral administration of 41BB agonistic Abs led to increases in CD8 T cell infiltration followed by tumor regression in murine models. We found that granulocytes and monocytes rapidly replaced macrophages and dendritic cells in tumors following administration of anti-41BB Abs. Overall, myeloid cells from anti-41BB–treated tumors had an improved capacity to stimulate T cells in comparison with control-treated tumors. In human coculture systems, we demonstrated that the agonism of the 41BB–41BBL axis enhanced costimulatory signals and effector functions among APC and autologous TILs. Overall, these findings suggest that the effect of 41BB agonistic Abs are supported by additional costimulatory signals from tumor-associated myeloid cells,v leading to enhanced TIL expansion and function.

Footnotes

  • This work was funded by the American Cancer Society (Leo and Anne Albert Charitable Foundation Research Scholar Grant RSG-16-117-01-LIB). A.A.S. was supported by the National Cancer Institute (NCI) (5K23CA178083). This work was also supported by the facilities of the H. Lee Moffitt Cancer Center and Research Institute and in part by NCI Cancer Center Support Grant P30 CA076292.

  • The online version of this article contains supplemental material.

  • Received June 26, 2020.
  • Accepted September 4, 2020.
  • Copyright © 2020 by The American Association of Immunologists, Inc.
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The Journal of Immunology: 208 (12)
The Journal of Immunology
Vol. 208, Issue 12
15 Jun 2022
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Intratumoral Activation of 41BB Costimulatory Signals Enhances CD8 T Cell Expansion and Modulates Tumor-Infiltrating Myeloid Cells
Patrick Innamarato, Sarah Asby, Jennifer Morse, Amy Mackay, MacLean Hall, Scott Kidd, Luz Nagle, Amod A. Sarnaik, Shari Pilon-Thomas
The Journal of Immunology October 5, 2020, ji2000759; DOI: 10.4049/jimmunol.2000759

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Intratumoral Activation of 41BB Costimulatory Signals Enhances CD8 T Cell Expansion and Modulates Tumor-Infiltrating Myeloid Cells
Patrick Innamarato, Sarah Asby, Jennifer Morse, Amy Mackay, MacLean Hall, Scott Kidd, Luz Nagle, Amod A. Sarnaik, Shari Pilon-Thomas
The Journal of Immunology October 5, 2020, ji2000759; DOI: 10.4049/jimmunol.2000759
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