Comparable transforming growth factor beta-mediated immune suppression in ex vivo-expanded natural killer cells from cord blood and peripheral blood: implications for adoptive immunotherapy

Kajal Chaudhry, Center for Cancer and Immunology Research, Children's National Hospital, 111 Michigan Ave NW, Washington, DC 20010, USA.
Ehsan Dowlati, Department of Neurosurgery, Georgetown University Medical Center, Washington, DC, USA.
Mark D. Long, Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA.
Ashley Geiger, Center for Cancer and Immunology Research, Children's National Hospital, 111 Michigan Ave NW, Washington, DC 20010, USA.
Haili Lang, Center for Cancer and Immunology Research, Children's National Hospital, 111 Michigan Ave NW, Washington, DC 20010, USA.
Eduardo C. Gomez, Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA.
Nethaji Muniraj, Center for Cancer and Immunology Research, Children's National Hospital, 111 Michigan Ave NW, Washington, DC 20010, USA.
Carlos E. Sanchez, Center for Cancer and Immunology Research, Children's National Hospital, 111 Michigan Ave NW, Washington, DC 20010, USA.
Prashant K. Singh, Genomics Shared Resource, Department of Cancer Genetics and Genomics, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA.
Song Liu, Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA.
Catherine M. Bollard, Center for Cancer and Immunology Research, Children's National Hospital, 111 Michigan Ave NW, Washington, DC 20010, USA; George Washington University Cancer Center, George Washington University, Washington, DC, USA. Electronic address: cbollard@childrensnational.org.
Conrad Russell Cruz, Center for Cancer and Immunology Research, Children's National Hospital, 111 Michigan Ave NW, Washington, DC 20010, USA; George Washington University Cancer Center, George Washington University, Washington, DC, USA. Electronic address: ccruz@childrensnational.org.

Document Type

Journal Article

Publication Date

5-16-2022

Journal

Cytotherapy

DOI

10.1016/j.jcyt.2022.04.001

Keywords

Cord blood NK cells; NK-cell immunotherapy; Peripheral blood NK cells; TGF-β

Abstract

T cell-based therapies like genetically modified immune cells expressing chimeric antigen receptors have shown robust anti-cancer activity in vivo, especially in patients with blood cancers. However, extending this approach to an "off-the-shelf" setting can be challenging, as allogeneic T cells carry a significant risk of graft-versus-host disease (GVHD). By contrast, allogeneic natural killer (NK) cells recognize malignant cells without the need for prior antigen exposure and have been used safely in multiple cancer settings without the risk of GVHD. However, similar to T cells, NK cell function is negatively impacted by tumor-induced transforming growth factor beta (TGF-β) secretion, which is a ubiquitous and potent immunosuppressive mechanism employed by most malignancies. Allogeneic NK cells for adoptive immunotherapy can be sourced from peripheral blood (PB) or cord blood (CB), and the authors' group and others have previously shown that ex vivo expansion and gene engineering can overcome CB-derived NK cells' functional immaturity and poor cytolytic activity, including in the presence of exogenous TGF-β. However, a direct comparison of the effects of TGF-β-mediated immune suppression on ex vivo-expanded CB- versus PB-derived NK cell therapy products has not previously been performed. Here the authors show that PB- and CB-derived NK cells have distinctive gene signatures that can be overcome by ex vivo expansion. Additionally, exposure to exogenous TGF-β results in an upregulation of inhibitory receptors on NK cells, a novel immunosuppressive mechanism not previously described. Finally, the authors provide functional and genetic evidence that both PB- and CB-derived NK cells are equivalently susceptible to TGF-β-mediated immune suppression. The authors believe these results provide important mechanistic insights to consider when using ex vivo-expanded, TGF-β-resistant PB- or CB-derived NK cells as novel immunotherapy agents for cancer.

Department

Pediatrics

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