A Fusion Protein Complex that Combines IL-12, IL-15, and IL-18 Signaling to Induce Memory-Like NK Cells for Cancer Immunotherapy

Becker-Hapak, Michelle; Shrestha, Niraj; McClain, Ethan; Dee, Michael J.; Chaturvedi, Pallavi; Leclerc, Gilles M.; Marsala, Lynne; Foster, Mark P.; Schappe, Timothy; Tran, Jennifer; Desai, Sweta; Neal, Carly C.; Pence, Patrick; Wong, Pamela; Wagner, Julia A.; Russler‐Germain, David A.; Zhu, Xiaoyun; Spanoudis, Catherine M.; Gallo, Victor L.; Echeverri, Christian A.; Ramirez, Laritza L.; You, Lijing; Egan, Jack O.; Rhode, Peter R.; Jiao, Jin-an; Muniz, Gabriela J.; Jeng, Emily K.; Prendes, Caitlin A.; Sullivan, Ryan P.; Berrien-Elliott, Melissa M.; Wong, Hing C.; Fehniger, Todd A.

doi:10.1158/2326-6066.cir-20-1002

Cited by 48 publications

(48 citation statements)

References 58 publications

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“…Due to their potent anti-tumor functions, the enhancement of NK cell activity against cancer is currently the focus of multiple therapeutic strategies. These include CAR-NK based approaches ( 11 , 12 ), agonistic antibodies ( 13 ), cytokine mediated stimulation ( 14 ) and checkpoint inhibitors ( 15 ). In addition to these direct approaches, NK cells can also contribute to the efficacy of other cancer therapies via the detection of altered activating and inhibitory ligand expression patterns on stressed tumor cells.…”

Section: Introductionmentioning

confidence: 99%

Selinexor Enhances NK Cell Activation Against Malignant B Cells via Downregulation of HLA-E

et al. 2021

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Selinexor is an FDA approved selective inhibitor of the nuclear export protein exportin-1 (XPO1) and causes specific cancer cell death via nuclear accumulation of tumor suppressor proteins. Design of rational studies for the use of selinexor in combination with other therapeutic agents, such as immunotherapies, requires a fundamental understanding of the effects of selinexor on the immune system. One important emerging area of immunotherapy are natural killer (NK) cell based therapeutics. NK cell function is tightly regulated by a balance of signals derived from multiple activating and inhibitory receptors. Thus in cancer, up-regulation of stress ligands recognised by activating receptors or down-regulation of HLA class I recognised by inhibitory receptors can result in an anti-cancer NK cell response. Changes in XPO1 function therefore have the potential to affect NK cell function through shifting this balance. We therefore sought to investigate how selinexor may affect NK cell function. Selinexor pre-treatment of lymphoma cells significantly increased NK cell mediated cytotoxicity against SU-DHL-4, JeKo-1 and Ramos cells, concurrent with increased CD107a and IFNγ expression on NK cells. In addition, selinexor enhanced ADCC against lymphoma cells coated with the anti-CD20 antibodies rituximab and obinutuzumab. In probing the likely mechanism, we identified that XPO1 inhibition significantly reduced the surface expression of HLA-E on lymphoma cell lines and on primary chronic lymphocytic leukemia cells. HLA-E binds the inhibitory receptor NKG2A and in accordance with this, selinexor selectively increased activation of NKG2A+ NK cells. Our data reveals that selinexor, in addition to its direct cytotoxic activity, also activates an anti-cancer immune response via disruption of the inhibitory NKG2A:HLA-E axis.

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Section: Introductionmentioning

confidence: 99%

Selinexor Enhances NK Cell Activation Against Malignant B Cells via Downregulation of HLA-E

et al. 2021

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“…One of the few evidences supporting this hypothesis was reported by Ni et al., who found that the conserved non-coding sequence 1 (CNS1) in the Ifng locus of IL-12/15/18-preactivated NK cells was demethylated 11 days after transferring these cells into RAG -/- γc -/- mice ( 60 ). Demethylated CNS1 in the Ifng locus was also found in human CIML NK cells after a resting period of 14 days ( 54 ). Additionally, it has been reported that the histone methyltransferase EZH2 plays a crucial role in CIML NK cells, since its pharmacological inhibition with UNC1999 limited the enhanced IFNγ production following IL-12/18-restimulation ( 61 ).…”

Section: Cytokine-induced Memory-like (Ciml) Nk Cellsmentioning

confidence: 99%

“…Specifically, IL-12/15/18-stimulated NK cells upregulate the expression of certain nutrient transporters, including the transferrin receptor CD71, the heavy subunit of multiple heterodimeric amino acid transporters CD98, and glucose transporters GLUT1 and GLUT3, and retain an elevated expression of CD98 and GLUT1 after a resting period ( 52 ). Moreover, upon IL-12/15/18 stimulation NK cells increase their metabolic activity and retain a metabolic profile shifted towards glycolysis for at least 7 days ( 52 – 54 ). Interestingly, inhibiting glycolytic activity with 2-DG during IL-12/15/18 stimulation resulted in a lower IFNγ production, both immediately after stimulation with cytokines and after a resting period of 6 days ( 53 , 55 ).…”

Section: Cytokine-induced Memory-like (Ciml) Nk Cellsmentioning

confidence: 99%

Cytokine-Induced Memory-Like NK Cells: From the Basics to Clinical Applications

et al. 2022

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Natural killer (NK) cells are lymphocytes with a key role in the defense against viral infections and tumor cells. Although NK cells are classified as innate lymphoid cells (ILCs), under certain circumstances they exhibit adaptive and memory-like features. The latter may be achieved, among others, by a brief stimulation with interleukin (IL)-12, IL-15 and IL-18. These cytokine-induced memory-like (CIML) NK cells resemble the trained immunity observed in myeloid cells. CIML NK cells undergo transcriptional, epigenetic and metabolic reprogramming that, along with changes in the expression of cell surface receptors and components of cytotoxic granules, are responsible for their enhanced effector functions after a resting period. In addition, these memory-like NK cells persist for a long time, which make them a good candidate for cancer immunotherapy. Currently, several clinical trials are testing CIML NK cells infusions to treat tumors, mostly hematological malignancies. In relapse/refractory acute myeloid leukemia (AML), the adoptive transfer of CIML NK cells is safe and complete clinical remissions have been observed. In our review, we sought to summarize the current knowledge about the generation and molecular basis of NK cell memory-like responses and the up-to-date results from clinical trials with CIML NK cells.

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“…In addition, IL-15 can increase the infiltration of NK cells in the tumor ( 190 ) and improve the survival rate in the treatment of GC liver metastasis–bearing mice ( 191 ). Primer of blood NK cells with recombinant human (rh)IL-12, rhIL-15, and rhIL-18 (12/15/18) can lead to memory-like NK cell differentiation and enhance tumor response ( 192 ). At the same time, increasing the immune clearance of NK cells against tumors can also play an anti-tumor effect.…”

Section: Immunotherapy Targeting Nk Cellsmentioning

confidence: 99%

Therapeutic strategies for gastric cancer targeting immune cells: Future directions

et al. 2022

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Gastric cancer (GC) is a malignancy with a high incidence and mortality, and the emergence of immunotherapy has brought survival benefits to GC patients. Compared with traditional therapy, immunotherapy has the advantages of durable response, long-term survival benefits, and lower toxicity. Therefore, targeted immune cells are the most promising therapeutic strategy in the field of oncology. In this review, we introduce the role and significance of each immune cell in the tumor microenvironment of GC and summarize the current landscape of immunotherapy in GC, which includes immune checkpoint inhibitors, adoptive cell therapy (ACT), dendritic cell (DC) vaccines, reduction of M2 tumor-associated macrophages (M2 TAMs), N2 tumor-associated neutrophils (N2 TANs), myeloid-derived suppressor cells (MDSCs), effector regulatory T cells (eTregs), and regulatory B cells (Bregs) in the tumor microenvironment and reprogram TAMs and TANs into tumor killer cells. The most widely used immunotherapy strategies are the immune checkpoint inhibitor programmed cell death 1/programmed death-ligand 1 (PD-1/PD-L1) antibody, cytotoxic T lymphocyte–associated protein 4 (CTLA-4) antibody, and chimeric antigen receptor T (CAR-T) in ACT, and these therapeutic strategies have significant anti-tumor efficacy in solid tumors and hematological tumors. Targeting other immune cells provides a new direction for the immunotherapy of GC despite the relatively weak clinical data, which have been confirmed to restore or enhance anti-tumor immune function in preclinical studies and some treatment strategies have entered the clinical trial stage, and it is expected that more and more effective immune cell–based therapeutic methods will be developed and applied.

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A Fusion Protein Complex that Combines IL-12, IL-15, and IL-18 Signaling to Induce Memory-Like NK Cells for Cancer Immunotherapy

Cited by 48 publications

References 58 publications

Selinexor Enhances NK Cell Activation Against Malignant B Cells via Downregulation of HLA-E

Selinexor Enhances NK Cell Activation Against Malignant B Cells via Downregulation of HLA-E

Cytokine-Induced Memory-Like NK Cells: From the Basics to Clinical Applications

Therapeutic strategies for gastric cancer targeting immune cells: Future directions

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