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Engineered murine IL-21-secreting leukemia cells induce granzyme B+ T cells and CD4+CD44+CD62L− effector memory cells while suppressing regulatory T cells, leading to long-term survival

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Abstract

We have explored the use of an IL-21 cell-based anti-leukemia treatment in a mouse model of acute lymphoblastic leukemia. 70Z/3 leukemia cells, engineered to secrete IL-21 and injected into the peritoneum of syngeneic mice, induced a strong anti-leukemia response resulting in 100% survival. Mice that mounted an IL-21-induced anti-leukemia immune response were immune to the parent cell line (no IL-21) when rechallenged.

Above a certain threshold, IL-21 secretion correlated with improved survival compared to mice injected with parent 70Z/3 cells. IL-21 was detected in serum with peak levels on day 7, correlating with the maximum expansion of IL-21-secreting 70Z/3 cells which subsequently were eliminated. Mice injected with IL-21-secreting leukemia cells had elevated numbers of granzyme B+ CD4+ and CD8+ T cells in the peritoneum, compared to mice injected with the parent cell line. Regulatory T cells, which increased greatly in 70Z/3-injected mice, failed to do so in mice injected with IL-21-secreting cells. Upon rechallenge, IL-21-primed mice went through a secondary immune response, primarily requiring CD4+ T cells, triggering a significant increase of CD4+CD44+CD62L− effector memory T cells. Adoptive transfer of T cells from IL21-primed/rechallenged hosts into naïve mice was successful, indicating that IL-21-primed antigen-experienced T cells convey immunity to naïve mice.

Our study shows that delivery of IL-21 in a cell-based anti-leukemia protocol has the potential to induce a potent immune response leading to cancer elimination and long-term immunity—properties which make IL-21 an attractive candidate for cancer immunotherapy. Protecting against tumor antigens as well as improving cancer immunity is justified, as current strategies are limited.

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Abbreviations

FCS:

Fetal calf serum

GFP:

Green fluorescent protein

GrzB:

Granzyme B

hr:

hour

IFN-γ:

Interferon-γ

ip:

Intraperitoneal

LV:

Lentivirus

LVV:

Lentiviral vector

ON:

Overnight

PBS:

Phosphate-buffered saline

vs:

versus

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Funding

This work was supported by funding from the Leukemia and Lymphoma Society of Canada, the Toronto General and Western Hospital Foundation, and the Princess Margaret Cancer Centre Foundation through grants held by Dr. Paige.

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Authors and Affiliations

  1. Princess Margaret Cancer Centre, University Health Network, Room 8-105, Toronto, ON, M5G 2M9, Canada

    Alexandra Berger, Sarah J. Colpitts, Morgan Zych & Christopher J. Paige

  2. Department of Immunology, Temerty Faculty of Medicine, University of Toronto, Toronto, Canada

    Sarah J. Colpitts & Christopher J. Paige

  3. Toronto General Hospital Research Institute, Ajmera Transplant Centre, University Health Network, Toronto, Canada

    Sarah J. Colpitts

  4. Department of Medical Biophysics, University of Toronto, Toronto, Canada

    Christopher J. Paige

Authors
  1. Alexandra Berger
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  2. Sarah J. Colpitts
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  4. Christopher J. Paige
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Contributions

AB, SJC, and MZ designed, carried out, and/or analyzed in vitro and in vivo experiments. AB, SJC, MZ and CJP wrote the manuscript. All authors read, revised, and approved the final manuscript.

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Correspondence to Alexandra Berger.

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Berger, A., Colpitts, S.J., Zych, M. et al. Engineered murine IL-21-secreting leukemia cells induce granzyme B+ T cells and CD4+CD44+CD62L− effector memory cells while suppressing regulatory T cells, leading to long-term survival. Cancer Immunol Immunother 72, 2597–2612 (2023). https://doi.org/10.1007/s00262-023-03442-2

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  • DOI: https://doi.org/10.1007/s00262-023-03442-2

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