Metabolic Reprograming via Deletion of CISH in Human iPSC-Derived NK Cells Promotes In Vivo Persistence and Enhances Anti-tumor Activity

Huang, Zhu; Blum, Robert; Bernareggi, Davide; Ask, Eivind Heggernes; Wu, ZhengMing; Hoel, Hanna Julie; Meng, Zhipeng; Wu, Chenming; Guan, Kun‐Liang; Malmberg, Karl‐Johan; Kaufman, Dan S.

doi:10.1016/j.stem.2020.05.008

Cited by 216 publications

(166 citation statements)

References 55 publications

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“…Similarly, Cish −/− NK cells proliferate better in response to low levels of IL‐15 and show greater anti‐tumor efficacy in multiple mouse models 74,75 . CISH −/− human NK cells derived from induced pluripotent stem cells (iPSCs) demonstrate superior killing of tumor cells due to an improved metabolic profile compared to WT cells 76 . Several groups have already demonstrated successful genetic targeting of CISH in human NK cells resulting in enhanced anti‐tumor efficacy using humanised tumor models 76,77 .…”

Section: Nk Cell Intracellular Checkpointsmentioning

confidence: 99%

Arrested development: suppression of NK cell function in the tumor microenvironment

2021

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Natural killer (NK) cells are cytotoxic innate lymphocytes that protect against viral infection and tumor metastasis. Despite their inherent ability to kill a broad range of virally infected, stressed and transformed cells, low numbers of dysfunctional NK cells are often observed in many advanced solid human cancers. Here, we review the potential mechanisms that influence suboptimal mature NK cell recruitment and function in the tumor microenvironment (TME) of solid tumors. We further highlight current immunotherapy approaches aimed to circumvent NK cell dysfunction and discuss next-generation strategies to enhance adoptive NK cell therapy through targeting intrinsic and extrinsic checkpoints the regulate NK cell functionality in the TME. Understanding the mechanisms that drive NK cell dysfunction in the TME will lead to novel immunotherapeutic approaches in the fight against cancer.

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Section: Nk Cell Intracellular Checkpointsmentioning

confidence: 99%

Arrested development: suppression of NK cell function in the tumor microenvironment

2021

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“…Another approach is to transduce the genes encoding IL-2 or IL-15 to enable self-production of these critical cytokines [161]. Similarly, genetic deletion of a negative regulator of IL-15 signaling, called cytokine-inducible SH2-containing protein or CIS, in iPSC-NK cells led to improved anti-tumor function, both in vitro and in vivo in a leukemia xenograft model [162]. The authors of this study showed that the CIS-deficient NK cells had improved metabolic fitness, caused by upregulated mTOR activity, suggesting that the mTOR inhibitors that are currently being trialed for various cancers may inadvertently dampen NK cell metabolic activity and therefore function.…”

Section: Genetic Modificationmentioning

confidence: 99%

Natural Killer Cells in Immunotherapy: Are We Nearly There?

Bachiller

Battram

Perez-Amill

et al. 2020

Cancers

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Natural killer (NK) cells are potent anti-tumor and anti-microbial cells of our innate immune system. They are equipped with a vast array of receptors that recognize tumor cells and other pathogens. The innate immune activity of NK cells develops faster than the adaptive one performed by T cells, and studies suggest an important immunoregulatory role for each population against the other. The association, observed in acute myeloid leukemia patients receiving haploidentical killer-immunoglobulin-like-receptor-mismatched NK cells, with induction of complete remission was the determinant to begin an increasing number of clinical studies administering NK cells for the treatment of cancer patients. Unfortunately, even though transfused NK cells demonstrated safety, their observed efficacy was poor. In recent years, novel studies have emerged, combining NK cells with other immunotherapeutic agents, such as monoclonal antibodies, which might improve clinical efficacy. Moreover, genetically-modified NK cells aimed at arming NK cells with better efficacy and persistence have appeared as another option. Here, we review novel pre-clinical and clinical studies published in the last five years administering NK cells as a monotherapy and combined with other agents, and we also review chimeric antigen receptor-modified NK cells for the treatment of cancer patients. We then describe studies regarding the role of NK cells as anti-microbial effectors, as lessons that we could learn and apply in immunotherapy applications of NK cells; these studies highlight an important immunoregulatory role performed between T cells and NK cells that should be considered when designing immunotherapeutic strategies. Lastly, we highlight novel strategies that could be combined with NK cell immunotherapy to improve their targeting, activity, and persistence.

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“…5a). CISH deletion has been shown to enhance NK cell metabolism 33 . To evaluate if this was also true in T cells, after expansion T cells from these six donors were subjected to metabolic analysis using Ultra-HPLC-MS/MS with or without TCR stimulation.…”

Section: Cish Ko Enhances T Cell Expansion and Function But Not Maturmentioning

confidence: 99%

Internal checkpoint regulates T cell neoantigen reactivity and susceptibility to PD1 blockade

Palmer

Webber

Patel

et al. 2020

Preprint

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While neoantigen-specific tumor infiltrating lymphocytes (TIL) can be derived from in antigen-expressing tumors, their adoptive transfer fails to consistently elicit durable tumor regression. There has been much focus on the role of activation/exhaustion markers such as PD1, CD39 and TOX in TIL senescence. We found these markers were inversely expressed to Cytokine-Induced SH2 protein (CISH), a negative regulator of TCR signaling and tumor immunity in mice. To evaluate the physiological role of CISH in human TIL we developed a high-efficiency CRIPSR-based method to knock out CISH in fully mature TIL. CISH KO resulted in increased T cell receptor (TCR) avidity, tumor cytolysis and neoantigen recognition. CISH expression in the tumor resections correlated with TIL inactivity against p53 hotspot mutations and CISH KO in TIL unmasked reactivity against these universal neoantigens. While CISH KO resulted in T cell hyperactivation and expansion it did not alter maturation, perhaps by preferential PLCγ-1 and not AKT inhibition. Lastly, CISH KO in T cells increased PD1 expression and the adoptive transfer of Cish KO T cells synergistically combines with PD1 antibody blockade resulting in durable tumor regression and survival in a preclinical animal model. These data offer new insights into the regulation of neoantigen recognition, expression of activation/exhaustion markers, and functional/maturation signals in tumor-specific T cells.

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Metabolic Reprograming via Deletion of CISH in Human iPSC-Derived NK Cells Promotes In Vivo Persistence and Enhances Anti-tumor Activity

Cited by 216 publications

References 55 publications

Arrested development: suppression of NK cell function in the tumor microenvironment

Arrested development: suppression of NK cell function in the tumor microenvironment

Natural Killer Cells in Immunotherapy: Are We Nearly There?

Internal checkpoint regulates T cell neoantigen reactivity and susceptibility to PD1 blockade

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