Natural killer cell dysfunction in cancer and new strategies to utilize NK cell potential for cancer immunotherapy

Zhang, Wanze; Zhao, Zhenghua; Li, Fan

doi:10.1016/j.molimm.2022.02.015

Cited by 33 publications

(24 citation statements)

References 152 publications

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“…In solid cancers, hypofunctional NK cells have been found both at tumor tissue and peripheral levels [136][137][138][139]. As shared features of cell anergy in cancers, NK cells have been reported have decreased levels of NKG2D (a major activator receptor), together with impaired degranulation capabilities and reduced production and release of cytolytic molecules, such as perforin, granzymes, and IFNγ (Figure 2I) [136,140]. NKG2D-deficient TRAMP mice exhibit three times fold increase in developing aggressive poorly differentiated prostate carcinoma, compared to NKG2D wild type (wt) TRAMP animals [141].…”

Section: Nk Cellsmentioning

confidence: 98%

The tumor innate immune microenvironment in prostate cancer: an overview of soluble factors and cellular effectors

Palano

Gallazzi

Cucchiara

et al. 2022

Exploration of Targeted Anti-Tumor Therapy

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Prostate cancer (PCa) accounts as the most common non-cutaneous disease affecting males, and as the first cancer, for incidence, in male. With the introduction of the concept of immunoscore, PCa has been classified as a cold tumor, thus driving the attention in the development of strategies aimed at blocking the infiltration/activation of immunosuppressive cells, while favoring the infiltration/activation of anti-tumor immune cells. Even if immunotherapy has revolutionized the approaches to cancer therapy, there is still a window failure, due to the immune cell plasticity within PCa, that can acquire pro-tumor features, subsequent to the tumor microenvironment (TME) capability to polarize them. This review discussed selected relevant soluble factors [transforming growth factor-beta (TGFβ), interleukin-6 (IL-6), IL-10, IL-23] and cellular components of the innate immunity, as drivers of tumor progression, immunosuppression, and angiogenesis within the PCa-TME.

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Section: Nk Cellsmentioning

confidence: 98%

The tumor innate immune microenvironment in prostate cancer: an overview of soluble factors and cellular effectors

Palano

Gallazzi

Cucchiara

et al. 2022

Exploration of Targeted Anti-Tumor Therapy

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“…For cancer immunotherapy, patient-derived NK cells function is usually hampered by curative treatments [ 168 ]. In fact, during tumor progression, the TME components can reduce NK cell capacity for proliferation, as well as ability of degranulation or cytokines secretion (such as TNF-α and IFN-γ) or expression of activating receptors [ 169 ]. Therefore, allogeneic NK cells are usually the first choice for cellular immunotherapy.…”

Section: Car-nk Cell Therapy In Solid Tumors: Applications Challenges...mentioning

confidence: 99%

CAR-cell therapy in the era of solid tumor treatment: current challenges and emerging therapeutic advances

et al. 2023

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In the last decade, Chimeric Antigen Receptor (CAR)-T cell therapy has emerged as a promising immunotherapeutic approach to fight cancers. This approach consists of genetically engineered immune cells expressing a surface receptor, called CAR, that specifically targets antigens expressed on the surface of tumor cells. In hematological malignancies like leukemias, myeloma, and non-Hodgkin B-cell lymphomas, adoptive CAR-T cell therapy has shown efficacy in treating chemotherapy refractory patients. However, the value of this therapy remains inconclusive in the context of solid tumors and is restrained by several obstacles including limited tumor trafficking and infiltration, the presence of an immunosuppressive tumor microenvironment, as well as adverse events associated with such therapy. Recently, CAR-Natural Killer (CAR-NK) and CAR-macrophages (CAR-M) were introduced as a complement/alternative to CAR-T cell therapy for solid tumors. CAR-NK cells could be a favorable substitute for CAR-T cells since they do not require HLA compatibility and have limited toxicity. Additionally, CAR-NK cells might be generated in large scale from several sources which would suggest them as promising off-the-shelf product. CAR-M immunotherapy with its capabilities of phagocytosis, tumor-antigen presentation, and broad tumor infiltration, is currently being investigated. Here, we discuss the emerging role of CAR-T, CAR-NK, and CAR-M cells in solid tumors. We also highlight the advantages and drawbacks of CAR-NK and CAR-M cells compared to CAR-T cells. Finally, we suggest prospective solutions such as potential combination therapies to enhance the efficacy of CAR-cells immunotherapy.

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“…NK cell triggers inflammatory responses including production of IFNγ and inflammatory cytokines upon activation, which further activates not only innate but also adaptive immunity including cytotoxic T cell (19)(20)(21). As NK cell was activated by ZL-1211 (Fig.…”

Section: Zl-1211 Induces Robust Nk Cell-mediated Inflammationmentioning

confidence: 99%

“…NK cell is an innate immune effector cell that can lyse cancer cells without prior activation (19)(20)(21). Upon activation NK cell releases lysis granules including perforin and granzyme that cooperatively induce cancer cell apoptosis.…”

Section: Authors' Disclosuresmentioning

confidence: 99%

ZL-1211 Exhibits Robust Antitumor Activity by Enhancing ADCC and Activating NK Cell–mediated Inflammation in CLDN18.2-High and -Low Expressing Gastric Cancer Models

Konno

Lin

et al. 2022

Cancer Research Communications

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CLDN18.2 (Claudin18.2)-targeting therapeutic antibodies have shown promising clinical efficacy in ~30% of gastric cancers expressing high levels of CLDN18.2 and less pronounced activity in low expressing malignancies. Here, we report that ZL-1211 is a monoclonal antibody targeting CLDN18.2 engineered to promote enhanced antibody-dependent cellular cytotoxicity (ADCC) with the goal of achieving more potent activity in a wider spectrum of high- and low-CLDN18.2 expressing tumors. ZL-1211 demonstrated more robust in vitro ADCC activity than clinical benchmark not only in CLDN18.2-high but also -low expressing gastric tumor cell lines. Greater anti-tumor efficacy was also observed in mouse xenograft models. Natural killer (NK) cell played critical roles in ZL-1211 efficacy and NK cell depletion abrogated ZL-1211-mediated ADCC activity in vitro. ZL-1211 efficacy in vivo was also dependent on the presence of an NK compartment. Strikingly, NK cells strongly induced an inflammatory response in response to ZL-1211 treatment, including increased IFNγ, TNFα, and IL-6 production, and were recruited into tumor microenvironment in patient-derived gastric tumors expressing CLDN18.2 upon ZL-1211 treatment to lyse the tumor cells. Taken together, our data suggest that ZL-1211 more effectively targets CLDN18.2-high gastric cancers as well as -low expressing malignancies that may not be eligible for treatment with the leading clinical benchmark by inducing enhanced ADCC response and activating NK cells with robust inflammation to enhance anti-tumor efficacy. Clinical activity of ZL-1211 is currently under evaluation in a Phase I clinical trial (NCT05065710).

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Natural killer cell dysfunction in cancer and new strategies to utilize NK cell potential for cancer immunotherapy

Cited by 33 publications

References 152 publications

The tumor innate immune microenvironment in prostate cancer: an overview of soluble factors and cellular effectors

The tumor innate immune microenvironment in prostate cancer: an overview of soluble factors and cellular effectors

CAR-cell therapy in the era of solid tumor treatment: current challenges and emerging therapeutic advances

ZL-1211 Exhibits Robust Antitumor Activity by Enhancing ADCC and Activating NK Cell–mediated Inflammation in CLDN18.2-High and -Low Expressing Gastric Cancer Models

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