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Murine regulatory T cells utilize granzyme B to promote tumor metastasis

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Abstract

Regulatory T cells (Tregs) possess a wide range of mechanisms for immune suppression. Among them, Granzyme B (GzmB) and perforin expressed by Tregs were shown to inhibit tumor clearance in previous reports, which contradicted the canonical roles of these cytotoxic molecules expressed by cytotoxic T cells and NK cells in antitumor immune responses. Given the ability of the tumor to manipulate the microenvironment, Treg-derived GzmB function may represent an important approach to aid in tumor growth as well as facilitating tumor metastasis. In this study, we utilized Treg-specific GzmB knockout (Foxp3creGzmBfl/fl) mice to test whether Treg-derived GzmB can aid in tumor progression and metastasis. Using an IL-2 complex to activate GzmB expression in the non-immunogenic B16-F10 tumor model, we provide evidence to show that GzmB produced by Tregs is important for spontaneous metastasis to the lungs. In addition, we depleted CD8 + T cells to selectively measure the impact of Treg-derived GzmB in an experimental lung metastasis model by intravenous injection of B16-F10 tumor cells; our results demonstrate that Treg-derived GzmB plays an important role in increasing the metastatic burden to the lungs.

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Data availability

The data sets used and/or analyzed during current study are available from the corresponding author upon reasonable request.

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Acknowledgements

This study was supported by funds through the National Cancer Institute (R01CA184728), Cancer Center Support Grant (P30CA134274), the National Institute of Allergy and Infectious Diseases (T32AI095190), and the Maryland Department of Health's Cigarette Restitution Fund (CRF) Program and used shared core facilities supported by University of Maryland Greenebaum Comprehensive Cancer Center (UMGCC) Support Grant (P30CA134274).

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Authors and Affiliations

  1. Department of Microbiology and Immunology, University of Maryland Baltimore, School of Medicine, Baltimore, MD, 21201, USA

    Ellis Tibbs & Xuefang Cao

  2. Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland Baltimore, Baltimore, USA

    Rakhee Rathnam Kalari Kandy, Delong Jiao, Long Wu & Xuefang Cao

Authors
  1. Ellis Tibbs
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  2. Rakhee Rathnam Kalari Kandy
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  3. Delong Jiao
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  4. Long Wu
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  5. Xuefang Cao
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Contributions

E.T. and X.C. designed the project, performed the experiments and wrote the manuscript. R.R.K.K., D.J. and L.W. performed in vivo tumor experiments. All authors reviewed the manuscript.

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Correspondence to Xuefang Cao.

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Tibbs, E., Kandy, R.R.K., Jiao, D. et al. Murine regulatory T cells utilize granzyme B to promote tumor metastasis. Cancer Immunol Immunother 72, 2927–2937 (2023). https://doi.org/10.1007/s00262-023-03410-w

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  • DOI: https://doi.org/10.1007/s00262-023-03410-w

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