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Adoptively transferred ex vivo expanded γδ-T cells mediate in vivo antitumor activity in preclinical mouse models of breast cancer

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Abstract

In contrast to antigen-specific αβ-T cells (adaptive immune system), γδ-T cells can recognize and lyse malignantly transformed cells almost immediately upon encounter in a manner that does not require the recognition of tumor-specific antigens (innate immune system). Given the well-documented capacity of γδ-T cells to innately kill a variety of malignant cells, efforts are now actively underway to exploit the antitumor properties of γδ-T cells for clinical purposes. Here, we present for the first time preclinical in vivo mouse models of γδ-T cell-based immunotherapy directed against breast cancer. These studies were explicitly designed to approximate clinical situations in which adoptively transferred γδ-T cells would be employed therapeutically against breast cancer. Using radioisotope-labeled γδ-T cells, we first show that adoptively transferred γδ-T cells localize to breast tumors in a mouse model (4T1 mammary adenocarcinoma) of human breast cancer. Moreover, by using an antibody directed against the γδ-T cell receptor (TCR), we determined that localization of adoptively transferred γδ-T cells to tumor is a TCR-dependant process. Additionally, biodistribution studies revealed that adoptively transferred γδ-T cells traffic differently in tumor-bearing mice compared to healthy mice with fewer γδ-T cells localizing into the spleens of tumor-bearing mice. Finally, in both syngeneic (4T1) and xenogeneic (2Lmp) models of breast cancer, we demonstrate that adoptively transferred γδ-T cells are both effective against breast cancer and are otherwise well-tolerated by treated animals. These findings provide a strong preclinical rationale for using ex vivo expanded adoptively transferred γδ-T cells as a form of cell-based immunotherapy for the treatment of breast cancer. Additionally, these studies establish that clinically applicable methods for radiolabeling γδ-T cells allows for the tracking of adoptively transferred γδ-T cells in tumor-bearing hosts.

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Acknowledgments

This work was supported by Grants 5P50CA089019-07 from the National Cancer Institute and the UAB Small Animal Imaging shared facility (P30CA013148). The authors thank Kyle Feeley for his thoughtful review of the manuscript.

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Authors and Affiliations

  1. Department of Medicine, Division of Hematology and Oncology, University of Alabama at Birmingham, SHEL 571, 1825 University Boulevard, Birmingham, AL, 35294, USA

    Benjamin H. Beck, Hyung-Gyoon Kim & Robin Shrestha

  2. Department of Radiology, University of Alabama at Birmingham, VH G082, 1670 University Boulevard, Birmingham, AL, 35294, USA

    Hyunki Kim, Sharon Samuel & Kurt Zinn

  3. Department of Surgery, University of Alabama at Birmingham, VH G082, 1670 University Boulevard, Birmingham, AL, 35294, USA

    Zhiyong Liu

  4. Department of Pediatrics, Division of Hematology and Oncology, University of Alabama at Birmingham, Children’s Hospital Room ACC-512, 1600 7th Avenue South, Birmingham, AL, 35233, USA

    Hilary Haines

  5. Department of Medicine, Division of Hematology and Oncology, Bone Marrow Transplantation Program, University of Alabama at Birmingham, THT-541, 1900 University Boulevard, Birmingham, AL, 35294, USA

    Richard D. Lopez

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  1. Benjamin H. Beck
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  2. Hyung-Gyoon Kim
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  3. Hyunki Kim
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  4. Sharon Samuel
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  8. Kurt Zinn
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  9. Richard D. Lopez
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Correspondence to Richard D. Lopez.

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Beck, B.H., Kim, HG., Kim, H. et al. Adoptively transferred ex vivo expanded γδ-T cells mediate in vivo antitumor activity in preclinical mouse models of breast cancer. Breast Cancer Res Treat 122, 135–144 (2010). https://doi.org/10.1007/s10549-009-0527-6

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  • DOI: https://doi.org/10.1007/s10549-009-0527-6

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