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Metabolic Reprograming Due to Deletion of CISH in Human Natural Killer Cells Promotes in vivo Persistence and Enhances Anti-Tumor Activity

59 Pages Posted: 3 Mar 2020 Publication Status: Review Complete

See all articles by Huang Zhu

Huang Zhu

University of California, San Diego (UCSD) - Division of Regenerative Medicine

Robert H. Blum

University of California, San Diego (UCSD) - Division of Regenerative Medicine

Davide Bernareggi

University of California, San Diego (UCSD) - Division of Regenerative Medicine

Eivind Heggernes Ask

University of Oslo - Department of Cancer Immunology; University of Oslo - The KG Jebsen Center for Cancer Immunotherapy

Zhengming Wu

University of California, San Diego (UCSD) - Moores Cancer Center

Hanna Julie Hoel

University of Oslo - Department of Cancer Immunology

Zhipeng Meng

University of California, San Diego (UCSD) - Moores Cancer Center

Chengsheng Wu

University of California, San Diego (UCSD) - Moores Cancer Center

Kun-Liang Guan

University of California, San Diego (UCSD) - Moores Cancer Center

Karl-Johan Malmberg

Karolinska Institutet - Center for Infectious Medicine; University of Oslo - Department of Cancer Immunology; University of Oslo - The KG Jebsen Center for Cancer Immunotherapy

Dan S. Kaufman

University of California, San Diego (UCSD) - Division of Regenerative Medicine

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Abstract

Cytokine-inducible SH2-containing protein (CIS, encoded by the gene CISH) is a key negative regulator of IL-15 signaling in natural killer (NK) cells. Here, we developed human CISH knockout (CISH-/-) NK cells using an induced pluripotent stem cell-derived NK cell (iPSC-NK cell) platform. CISH-/- iPSC-derived NK cells demonstrate increased IL-15 mediated JAK-STAT pathway signaling activity. Consequently CISH-/- iPSC-NK cells exhibit improved expansion and increased cytotoxic activity against multiple tumor cell lines when maintained at low cytokine concentration. CISH-/- iPSC-NK cells display significantly increased in vivo persistence and inhibition of tumor progression in a leukemia xenograft model. Mechanistically, CISH-/- iPSC-NK cells display improved metabolic fitness characterized by a significant increase in basal glycolysis, glycolytic capacity, maximal mitochondrial respiration, ATP-linked respiration and spare capacity respiration which are mediated by mTOR signaling and directly contribute to enhanced NK cell function. In addition, we demonstrate that deletion of CISH in human NK cells increases single-cell polyfunctionality by secreting multiple effector cytokines, a profile has been proven to be positively associated with clinical outcome of CAR-T cells. Together, these studies demonstrate CIS plays a key role to regulate human NK cell metabolic activity and deletion of CIS leads to enhanced anti-tumor activity.

Keywords: iPSCs, natural killer cells, cell metabolism, Cytokine-inducible SH2-containing protein (CISH), immunotherapy, cell therapy, cellular engineering

Suggested Citation

Zhu, Huang and Blum, Robert H. and Bernareggi, Davide and Ask, Eivind Heggernes and Wu, Zhengming and Hoel, Hanna Julie and Meng, Zhipeng and Wu, Chengsheng and Guan, Kun-Liang and Malmberg, Karl-Johan and Kaufman, Dan S., Metabolic Reprograming Due to Deletion of CISH in Human Natural Killer Cells Promotes in vivo Persistence and Enhances Anti-Tumor Activity. Available at SSRN: https://ssrn.com/abstract=3544410 or http://dx.doi.org/10.2139/ssrn.3544410
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Huang Zhu

University of California, San Diego (UCSD) - Division of Regenerative Medicine ( email )

United States

Robert H. Blum

University of California, San Diego (UCSD) - Division of Regenerative Medicine ( email )

United States

Davide Bernareggi

University of California, San Diego (UCSD) - Division of Regenerative Medicine ( email )

United States

Eivind Heggernes Ask

University of Oslo - Department of Cancer Immunology

Kirkeveien 166
Building 2H
Oslo, N-0450
Norway

University of Oslo - The KG Jebsen Center for Cancer Immunotherapy

Kirkeveien 166
Building 2H
Oslo, N-0450
Norway

Zhengming Wu

University of California, San Diego (UCSD) - Moores Cancer Center

1503, 3855 Health Sciences Dr.
La Jolla, CA 92093
United States

Hanna Julie Hoel

University of Oslo - Department of Cancer Immunology ( email )

Kirkeveien 166
Building 2H
Oslo, N-0450
Norway

Zhipeng Meng

University of California, San Diego (UCSD) - Moores Cancer Center ( email )

1503, 3855 Health Sciences Dr.
La Jolla, CA 92093
United States

Chengsheng Wu

University of California, San Diego (UCSD) - Moores Cancer Center ( email )

1503, 3855 Health Sciences Dr.
La Jolla, CA 92093
United States

Kun-Liang Guan

University of California, San Diego (UCSD) - Moores Cancer Center ( email )

1503, 3855 Health Sciences Dr.
La Jolla, CA 92093
United States

Karl-Johan Malmberg

Karolinska Institutet - Center for Infectious Medicine ( email )

Granits väg 4
Solna, Stockholm 17171
Sweden

University of Oslo - Department of Cancer Immunology ( email )

Kirkeveien 166
Building 2H
Oslo, N-0450
Norway

University of Oslo - The KG Jebsen Center for Cancer Immunotherapy ( email )

Kirkeveien 166
Building 2H
Oslo, N-0450
Norway

Dan S. Kaufman (Contact Author)

University of California, San Diego (UCSD) - Division of Regenerative Medicine ( email )

United States

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