Acquired Natural Killer Cell Dysfunction in the Tumor Microenvironment of Classic Hodgkin Lymphoma

Chiu, Jodi; Ernst, Daniël; Keating, Armand

doi:10.3389/fimmu.2018.00267

Cited by 62 publications

(56 citation statements)

References 110 publications

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“…A phase I study for relapsed/refractory AML patients using MEN1112 (NCT02353143) is expected to shed light on its tolerability and potential future use in single/combination therapy. NK cells are largely excluded from the TME in HL, and peripheral blood and tumor infiltrating NK cells from HL patients are severely impaired (237). Therefore, enhancing their activity in HL may greatly benefit treatment.…”

Section: Mabs In Clinical Trials-targeting Tumor Ligands For Optimizamentioning

confidence: 99%

Unleashing Natural Killer Cells in the Tumor Microenvironment–The Next Generation of Immunotherapy?

2020

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The emergence of immunotherapy for cancer treatment bears considerable clinical promise. Nevertheless, many patients remain unresponsive, acquire resistance, or suffer dose-limiting toxicities. Immune-editing of tumors assists their escape from the immune system, and the tumor microenvironment (TME) induces immune suppression through multiple mechanisms. Immunotherapy aims to bolster the activity of immune cells against cancer by targeting these suppressive immunomodulatory processes. Natural Killer (NK) cells are a heterogeneous subset of immune cells, which express a diverse array of activating and inhibitory germline-encoded receptors, and are thus capable of directly targeting and killing cancer cells without the need for MHC specificity. Furthermore, they play a critical role in triggering the adaptive immune response. Enhancing the function of NK cells in the context of cancer is therefore a promising avenue for immunotherapy. Different NK-based therapies have been evaluated in clinical trials, and some have demonstrated clinical benefits, especially in the context of hematological malignancies. Solid tumors remain much more difficult to treat, and the time point and means of intervention of current NK-based treatments still require optimization to achieve long term effects. Here, we review recently described mechanisms of cancer evasion from NK cell immune surveillance, and the therapeutic approaches that aim to potentiate NK function. Specific focus is placed on the use of specialized monoclonal antibodies against moieties on the cancer cell, or on both the tumor and the NK cell. In addition, we highlight newly identified mechanisms that inhibit NK cell activity in the TME, and describe how biochemical modifications of the TME can synergize with current treatments and increase susceptibility to NK cell activity.

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Section: Mabs In Clinical Trials-targeting Tumor Ligands For Optimizamentioning

confidence: 99%

Unleashing Natural Killer Cells in the Tumor Microenvironment–The Next Generation of Immunotherapy?

2020

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“…The immunosuppressive nature of the TME in cHL specifically depends on the inhibition of the proliferation and activity of the natural killer (NK) cells, which contribute to the tumour immune escape mechanisms. Locally, the HRS cells and the cells from the TME express ligands for inhibitory receptors on NK cells, including HLA‐E, HLA‐G, and PD‐L1 . In addition, the infiltrating lymphocytes in the micro‐environment of solid tumour, mainly CD8 + T cells, recognize the tumour antigen by MHC‐I on APCs.…”

Section: The Immune Escape Mechanism Of Hrs Cells In Chlmentioning

confidence: 99%

Epigenetic abnormalities of classical Hodgkin lymphoma and its effect on immune escape

Liu

Huang

Liu

et al. 2019

Cell Biochemistry & Function

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Classical Hodgkin lymphoma (cHL) is a particular kind of malignant tumour that originates from the B cells. The malignant phenotype of cHL is, at least in part, maintained by epigenetic aberrations, which primarily consist of abnormal histone methylation and acetylation. Progress has been made in clinical trials concerning the histone deacetylases inhibitors (HDACis) in cHL. Also, some demethylation regimens could serve the purpose of preventing and treating tumours. Programmed death-ligand receptor 1 (PD-L1, CD274) inhibitors or apoptosis receptor 1 (PD-1, CD279) inhibitors are used in treating patients with relapsed cHL in recent years. Academic researches indicated that PD-1/PD-L1 inhibitors, including nivolumab and pembrolizumab, demonstrate remarkable activity in relapsed cHL. In addition, in recent years, a close association between epigenetic aberrations and immune escape has been explored in cHL. DNA methyltransferase (DNMT) inhibitors, HDACis, and immune checkpoint blockade exhibit synergistic effects. Thus, this review aims to provide an overview on the epigenetic abnormalities of cHL and its effect on immune escape, in order to explore the optimal combination approach to treat the disease.Significance of the study: Cancer Statistics 2018 reported that more than 8000 new cases of Hodgkin lymphoma were diagnosed. In recent years, PD-1/PD-L1 inhibitors for cHL have been utilized, and the therapeutic strategies of HDACis combined with PD-1/PD-L1 inhibitors have been raised. It is critical for improving the efficacy and decreasing the toxicity in treating the patients with cHL.

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“…In patients with HL, studies have shown that: (1) the immunosuppressive nature of the TME speci ically inhibits proliferation and activity of NK cells, (2) malignant Reed-Sternberg cells and other components of the TME express ligands to inhibit NK cells, and (3) although NK cell de iciency begins at the tumor site, ultimately it progresses systematically in patients with advanced disease as the secretion of cytokines and chemokines mediates the systemic immunosuppression. Thus, strategies to reactivate NK cell function or those aimed at blocking the evasive mechanisms displayed by the TME may ultimately identify new immunotherapeutic targets [230,231]. In patients with HL, CD 123 (IL-3Rα) is frequently expressed by malignant cells and the combination of NK cells and the fully humanized anti-CD 123 monoclonal antibody (CSL362) represents a promising future therapeutic strategy [144].…”

Section: Nk Cells In Lymphomasmentioning

confidence: 99%

Natural killer cells in patients with hematologic malignancies, solid tumors and in recipients of hematopoietic stem cell transplantation

Ka¹,

Al-Jasser²,

Wk³

2019

J Stem Cell Ther Transplant

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Acquired Natural Killer Cell Dysfunction in the Tumor Microenvironment of Classic Hodgkin Lymphoma

Cited by 62 publications

References 110 publications

Unleashing Natural Killer Cells in the Tumor Microenvironment–The Next Generation of Immunotherapy?

Unleashing Natural Killer Cells in the Tumor Microenvironment–The Next Generation of Immunotherapy?

Epigenetic abnormalities of classical Hodgkin lymphoma and its effect on immune escape

Natural killer cells in patients with hematologic malignancies, solid tumors and in recipients of hematopoietic stem cell transplantation

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