2. Academic Validation
  3. Therapeutic application of human type 2 innate lymphoid cells via induction of granzyme B-mediated tumor cell death

Therapeutic application of human type 2 innate lymphoid cells via induction of granzyme B-mediated tumor cell death

  • Cell. 2024 Jan 5:S0092-8674(23)01347-8. doi: 10.1016/j.cell.2023.12.015.
Zhenlong Li 1,  Rui Ma 1,  Hejun Tang 1,  Jiamin Guo 2,  Zahir Shah 1,  Jianying Zhang 3,  Ningyuan Liu 1,  Shuai Cao 1,  Guido Marcucci 4,  David Artis 5,  Michael A Caligiuri 6,  Jianhua Yu 7
Affiliations

Affiliations

  • 1 Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA 91010, USA; Hematologic Malignancies Research Institute, City of Hope National Medical Center, Los Angeles, CA 91010, USA.
  • 2 Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA 91010, USA; Irell & Manella Graduate School of Biological Sciences, Beckman Research Institute, City of Hope, Los Angeles, CA 91010, USA.
  • 3 Department of Computational and Quantitative Medicine, City of Hope National Medical Center, Los Angeles, CA 91010, USA.
  • 4 Gehr Family Center for Leukemia Research, Hematologic Malignancies Research Institute, Department of Hematologic Malignancies Translational Science, City of Hope National Medical Center, Los Angeles, CA 91010, USA.
  • 5 Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, New York, NY 10021, USA.
  • 6 Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA 91010, USA; Hematologic Malignancies Research Institute, City of Hope National Medical Center, Los Angeles, CA 91010, USA; City of Hope Comprehensive Cancer Center, Los Angeles, CA 91010, USA. Electronic address: mcaligiuri@coh.org.
  • 7 Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA 91010, USA; Hematologic Malignancies Research Institute, City of Hope National Medical Center, Los Angeles, CA 91010, USA; City of Hope Comprehensive Cancer Center, Los Angeles, CA 91010, USA; Department of Immuno-Oncology, City of Hope, Los Angeles, CA 91010, USA. Electronic address: jiayu@coh.org.
PMID: 38211590 DOI: 10.1016/j.cell.2023.12.015
Abstract

The therapeutic potential for human type 2 innate lymphoid cells (ILC2s) has been underexplored. Although not observed in mouse ILC2s, we found that human ILC2s secrete granzyme B (GZMB) and directly lyse tumor cells by inducing Pyroptosis and/or Apoptosis, which is governed by a DNAM-1-CD112/CD155 interaction that inactivates the negative regulator FOXO1. Over time, the high surface density expression of CD155 in acute myeloid leukemia cells impairs the expression of DNAM-1 and GZMB, thus allowing for immune evasion. We describe a reliable platform capable of up to 2,000-fold expansion of human ILC2s within 4 weeks, whose molecular and cellular ILC2 profiles were validated by single-cell RNA Sequencing. In both leukemia and solid tumor models, exogenously administered expanded human ILC2s show significant antitumor effects in vivo. Collectively, we demonstrate previously unreported properties of human ILC2s and identify this innate immune cell subset as a member of the cytolytic immune effector cell family.

Keywords

DNAM-1; GZMB; ILC2s; apoptosis; cancer immunotherapy; cell therapy; innate lymphoid cells; leukemia; pyroptosis; solid tumors.

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