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20 pages, 7065 KiB

Open AccessArticle

Alterations in Natural Killer Cells in Colorectal Cancer Patients with Stroma AReactive Invasion Front Areas (SARIFA)

by Nic G. Reitsam, Bruno Märkl, Sebastian Dintner, Eva Sipos, Przemyslaw Grochowski, Bianca Grosser, Florian Sommer, Stefan Eser, Pia Nerlinger, Frank Jordan, Andreas Rank, Phillip Löhr and Johanna Waidhauser

Cancers 2023, 15(3), 994; https://doi.org/10.3390/cancers15030994 - 03 Feb 2023

Cited by 8 | Viewed by 2118

Abstract

Background: Recently, our group introduced Stroma AReactive Invasion Front Areas (SARIFA) as an independent prognostic predictor for a poorer outcome in colon cancer patients, which is probably based on immunologic alterations combined with a direct tumor-adipocyte interaction: the two together reflecting a distinct [...] Read more.

Background: Recently, our group introduced Stroma AReactive Invasion Front Areas (SARIFA) as an independent prognostic predictor for a poorer outcome in colon cancer patients, which is probably based on immunologic alterations combined with a direct tumor-adipocyte interaction: the two together reflecting a distinct tumor biology. Considering it is already known that peripheral immune cells are altered in colorectal cancer (CRC) patients, this study aims to investigate the changes in lymphocyte subsets in SARIFA-positive cases and correlate these changes with the local immune response. Methods: Flow cytometry was performed to analyze B, T, and natural killer (NK) cells in the peripheral blood (PB) of 45 CRC patients. Consecutively, lymphocytes in PB, tumor-infiltrating lymphocytes (TILs), and CD56+ and CD57+ lymphocytes at the invasion front and the tumor center were compared between patients with SARIFA-positive and SARIFA-negative CRCs. Results: Whereas no differences could be observed regarding most PB lymphocyte populations as well as TILs, NK cells were dramatically reduced in the PB of SARIFA-positive cases. Moreover, CD56 and CD57 immunohistochemistry suggested SARIFA-status-dependent changes regarding NK cells and NK-like lymphocytes in the tumor microenvironment. Conclusion: This study proves that our newly introduced biomarker, SARIFA, comes along with distinct immunologic alterations, especially regarding NK cells. Full article

(This article belongs to the Special Issue Natural Killer Cells in Cancer Biology and Therapy)

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12 pages, 2486 KiB

Open AccessArticle

Deletion of Glycogen Synthase Kinase 3 Beta Reprograms NK Cell Metabolism

by Marcelo S. F. Pereira, Kinnari Sorathia, Yasemin Sezgin, Aarohi Thakkar, Colin Maguire, Patrick L. Collins, Bethany L. Mundy-Bosse, Dean A. Lee and Meisam Naeimi Kararoudi

Cancers 2023, 15(3), 705; https://doi.org/10.3390/cancers15030705 - 24 Jan 2023

Cited by 1 | Viewed by 2556

Abstract

Loss of cytotoxicity and defective metabolism are linked to glycogen synthase kinase 3 beta (GSK3β) overexpression in natural killer (NK) cells from patients with acute myeloid leukemia or from healthy donors after expansion ex vivo with IL-15. Drug inhibition of GSK3β in these [...] Read more.

Loss of cytotoxicity and defective metabolism are linked to glycogen synthase kinase 3 beta (GSK3β) overexpression in natural killer (NK) cells from patients with acute myeloid leukemia or from healthy donors after expansion ex vivo with IL-15. Drug inhibition of GSK3β in these NK cells improves their maturation and cytotoxic activity, but the mechanisms of GSK3β-mediated dysfunction have not been well studied. Here, we show that expansion of NK cells with feeder cells expressing membrane-bound IL-21 maintained normal GSK3β levels, allowing us to study GSK3β function using CRISPR gene editing. We deleted GSK3B and expanded paired-donor knockout and wild-type (WT) NK cells and then assessed transcriptional and functional alterations induced by loss of GSK3β. Surprisingly, our data showed that deletion of GSK3B did not alter cytotoxicity, cytokine production, or maturation (as determined by CD57 expression). However, GSK3B-KO cells demonstrated significant changes in expression of genes related to rRNA processing, cell proliferation, and metabolic function, suggesting possible metabolic reprogramming. Next, we found that key genes downregulated in GSK3B-KO NK cells were upregulated in GSK3β-overexpressing NK cells from AML patients, confirming this correlation in a clinical setting. Lastly, we measured cellular energetics and observed that GSK3B-KO NK cells exhibited 150% higher spare respiratory capacity, a marker of metabolic fitness. These findings suggest a role for GSK3β in regulating NK cell metabolism. Full article

(This article belongs to the Special Issue Natural Killer Cells in Cancer Biology and Therapy)

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15 pages, 2283 KiB

Open AccessArticle

Defective DNAM-1 Dependent Cytotoxicity in Hepatocellular Carcinoma-Infiltrating NK Cells

by Stefania Mantovani, Stefania Varchetta, Dalila Mele, Roberta Maiello, Matteo Donadon, Cristiana Soldani, Barbara Franceschini, Guido Torzilli, Giuseppe Tartaglia, Marcello Maestri, Gaetano Piccolo, Matteo Barabino, Enrico Opocher, Stefano Bernuzzi, Mario U. Mondelli and Barbara Oliviero

Cancers 2022, 14(16), 4060; https://doi.org/10.3390/cancers14164060 - 22 Aug 2022

Cited by 1 | Viewed by 1874

Abstract

Background: Natural killer (NK) cells play a key role in immune surveillance and response to tumors, their function regulated by NK cell receptors and their ligands. The DNAM-1 activating receptor recognizes the CD155 molecule expressed in several tumor cells, such as hepatocellular carcinoma [...] Read more.

Background: Natural killer (NK) cells play a key role in immune surveillance and response to tumors, their function regulated by NK cell receptors and their ligands. The DNAM-1 activating receptor recognizes the CD155 molecule expressed in several tumor cells, such as hepatocellular carcinoma (HCC). This study aims to investigate the role of the DNAM-1/CD155 axis in mediating the NK cell response in patients with HCC. Methods: Soluble CD155 was measured by ELISA. CD155 expression was sought in HCC cells by immunohistochemistry, qPCR, and flow cytometry. DNAM-1 modulation in NK cells was evaluated in transwell experiments and by a siRNA-mediated knockdown. NK cell functions were examined by direct DNAM-1 triggering. Results: sCD155 was increased in sera from HCC patients and correlated with the parameters of an advanced disease. The expression of CD155 in HCC showed a positive trend toward better overall survival. DNAM-1 downmodulation was induced by CD155-expressing HCC cells, in agreement with lower DNAM-1 expressions in tumor-infiltrating NK (NK-TIL) cells. DNAM-1-mediated cytotoxicity was defective both in circulating NK cells and in NK-TIL of HCC patients. Conclusions: We provide evidence of alterations in the DNAM-1/CD155 axis in HCC, suggesting a possible mechanism of tumor resistance to innate immune surveillance. Full article

(This article belongs to the Special Issue Natural Killer Cells in Cancer Biology and Therapy)

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Review

Jump to: Research

20 pages, 2244 KiB

Open AccessReview

Addressing Natural Killer Cell Dysfunction and Plasticity in Cell-Based Cancer Therapeutics

by Kassandra M. Coyle, Lindsey G. Hawke and Mark L. Ormiston

Cancers 2023, 15(6), 1743; https://doi.org/10.3390/cancers15061743 - 13 Mar 2023

Cited by 3 | Viewed by 2781

Abstract

Natural killer (NK) cells are cytotoxic group 1 innate lymphoid cells (ILC), known for their role as killers of stressed, cancerous, and virally infected cells. Beyond this cytotoxic function, NK cell subsets can influence broader immune responses through cytokine production and have been [...] Read more.

Natural killer (NK) cells are cytotoxic group 1 innate lymphoid cells (ILC), known for their role as killers of stressed, cancerous, and virally infected cells. Beyond this cytotoxic function, NK cell subsets can influence broader immune responses through cytokine production and have been linked to central roles in non-immune processes, such as the regulation of vascular remodeling in pregnancy and cancer. Attempts to exploit the anti-tumor functions of NK cells have driven the development of various NK cell-based therapies, which have shown promise in both pre-clinical disease models and early clinical trials. However, certain elements of the tumor microenvironment, such as elevated transforming growth factor (TGF)-β, hypoxia, and indoalemine-2,3-dioxygenase (IDO), are known to suppress NK cell function, potentially limiting the longevity and activity of these approaches. Recent studies have also identified these factors as contributors to NK cell plasticity, defined by the conversion of classical cytotoxic NK cells into poorly cytotoxic, tissue-resident, or ILC1-like phenotypes. This review summarizes the current approaches for NK cell-based cancer therapies and examines the challenges presented by tumor-linked NK cell suppression and plasticity. Ongoing efforts to overcome these challenges are discussed, along with the potential utility of NK cell therapies to applications outside cancer. Full article

(This article belongs to the Special Issue Natural Killer Cells in Cancer Biology and Therapy)

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26 pages, 1318 KiB

Open AccessReview

Natural Killer Cells in Chronic Lymphocytic Leukemia: Functional Impairment and Therapeutic Potential

by Max Yano, John C. Byrd and Natarajan Muthusamy

Cancers 2022, 14(23), 5787; https://doi.org/10.3390/cancers14235787 - 24 Nov 2022

Cited by 7 | Viewed by 1927

Abstract

Immunotherapy approaches have advanced rapidly in recent years. While the greatest therapeutic advances so far have been achieved with T cell therapies such as immune checkpoint blockade and CAR-T, recent advances in NK cell therapy have highlighted the therapeutic potential of these cells. [...] Read more.

Immunotherapy approaches have advanced rapidly in recent years. While the greatest therapeutic advances so far have been achieved with T cell therapies such as immune checkpoint blockade and CAR-T, recent advances in NK cell therapy have highlighted the therapeutic potential of these cells. Chronic lymphocytic leukemia (CLL), the most prevalent form of leukemia in Western countries, is a very immunosuppressive disease but still shows significant potential as a target of immunotherapy, including NK-based therapies. In addition to their antileukemia potential, NK cells are important immune effectors in the response to infections, which represent a major clinical concern for CLL patients. Here, we review the interactions between NK cells and CLL, describing functional changes and mechanisms of CLL-induced NK suppression, interactions with current therapeutic options, and the potential for therapeutic benefit using NK cell therapies. Full article

(This article belongs to the Special Issue Natural Killer Cells in Cancer Biology and Therapy)

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33 pages, 1699 KiB

Open AccessReview

Natural Killer Cells: A Promising Kit in the Adoptive Cell Therapy Toolbox

by Jiani Xiao, Tianxiang Zhang, Fei Gao, Zhengwei Zhou, Guang Shu, Yizhou Zou and Gang Yin

Cancers 2022, 14(22), 5657; https://doi.org/10.3390/cancers14225657 - 17 Nov 2022

Cited by 3 | Viewed by 5288

Abstract

As an important component of the innate immune system, natural killer (NK) cells have gained increasing attention in adoptive cell therapy for their safety and efficacious tumor-killing effect. Unlike T cells which rely on the interaction between TCRs and specific peptide-MHC complexes, NK [...] Read more.

As an important component of the innate immune system, natural killer (NK) cells have gained increasing attention in adoptive cell therapy for their safety and efficacious tumor-killing effect. Unlike T cells which rely on the interaction between TCRs and specific peptide-MHC complexes, NK cells are more prone to be served as “off-the-shelf” cell therapy products due to their rapid recognition and killing of tumor cells without MHC restriction. In recent years, constantly emerging sources of therapeutic NK cells have provided flexible options for cancer immunotherapy. Advanced genetic engineering techniques, especially chimeric antigen receptor (CAR) modification, have yielded exciting effectiveness in enhancing NK cell specificity and cytotoxicity, improving in vivo persistence, and overcoming immunosuppressive factors derived from tumors. In this review, we highlight current advances in NK-based adoptive cell therapy, including alternative sources of NK cells for adoptive infusion, various CAR modifications that confer different targeting specificity to NK cells, multiple genetic engineering strategies to enhance NK cell function, as well as the latest clinical research on adoptive NK cell therapy. Full article

(This article belongs to the Special Issue Natural Killer Cells in Cancer Biology and Therapy)

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24 pages, 3459 KiB

Open AccessReview

Nanoparticle Enhancement of Natural Killer (NK) Cell-Based Immunotherapy

by Dhanashree Murugan, Vasanth Murugesan, Balaji Panchapakesan and Loganathan Rangasamy

Cancers 2022, 14(21), 5438; https://doi.org/10.3390/cancers14215438 - 04 Nov 2022

Cited by 8 | Viewed by 3110

Abstract

Natural killer (NK) cells are one of the first lines of defense against infections and malignancies. NK cell-based immunotherapies are emerging as an alternative to T cell-based immunotherapies. Preclinical and clinical studies of NK cell-based immunotherapies have given promising results in the past [...] Read more.

Natural killer (NK) cells are one of the first lines of defense against infections and malignancies. NK cell-based immunotherapies are emerging as an alternative to T cell-based immunotherapies. Preclinical and clinical studies of NK cell-based immunotherapies have given promising results in the past few decades for hematologic malignancies. Despite these achievements, NK cell-based immunotherapies have limitations, such as limited performance/low therapeutic efficiency in solid tumors, the short lifespan of NK cells, limited specificity of adoptive transfer and genetic modification, NK cell rejection by the patient’s immune system, insignificant infiltration of NK cells into the tumor microenvironment (TME), and the expensive nature of the treatment. Nanotechnology could potentially assist with the activation, proliferation, near-real time imaging, and enhancement of NK cell cytotoxic activity by guiding their function, analyzing their performance in near-real time, and improving immunotherapeutic efficiency. This paper reviews the role of NK cells, their mechanism of action in killing tumor cells, and the receptors which could serve as potential targets for signaling. Specifically, we have reviewed five different areas of nanotechnology that could enhance immunotherapy efficiency: nanoparticle-assisted immunomodulation to enhance NK cell activity, nanoparticles enhancing homing of NK cells, nanoparticle delivery of RNAi to enhance NK cell activity, genetic modulation of NK cells based on nanoparticles, and nanoparticle activation of NKG2D, which is the master regulator of all NK cell responses. Full article

(This article belongs to the Special Issue Natural Killer Cells in Cancer Biology and Therapy)

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21 pages, 904 KiB

Open AccessReview

Cord Blood-Derived Natural Killer Cell Exploitation in Immunotherapy Protocols: More Than a Promise?

by Laura Damele, Grazia Maria Spaggiari, Monica Parodi, Maria Cristina Mingari, Massimo Vitale and Chiara Vitale

Cancers 2022, 14(18), 4439; https://doi.org/10.3390/cancers14184439 - 13 Sep 2022

Cited by 7 | Viewed by 2757

Abstract

In the last 20 years, Natural Killer (NK) cell-based immunotherapy has become a promising approach to target various types of cancer. Indeed, NK cells play a pivotal role in the first-line defense against tumors through major histocompatibility complex-independent immunosurveillance. Their role in the [...] Read more.

In the last 20 years, Natural Killer (NK) cell-based immunotherapy has become a promising approach to target various types of cancer. Indeed, NK cells play a pivotal role in the first-line defense against tumors through major histocompatibility complex-independent immunosurveillance. Their role in the control of leukemia relapse has been clearly established and, moreover, the presence of NK cells in the tumor microenvironment (TME) generally correlates with good prognosis. However, it has also been observed that, often, NK cells poorly infiltrate the tumor tissue, and, in TME, their functions may be compromised by immunosuppressive factors that contribute to the failure of anti-cancer immune response. Currently, studies are focused on the design of effective strategies to expand NK cells and enhance their cytotoxic activity, exploiting different cell sources, such as peripheral blood (PB), umbilical cord blood (UCB) and NK cell lines. Among them, UCB represents an important source of mature NK cells and CD34⁺ Hematopoietic Stem and Progenitor Cells (HSPCs), as precursors of NK cells. In this review, we summarize the UCB-derived NK cell activity in the tumor context, review the different in-vitro models to expand NK cells from UCB, and discuss the importance of their exploitation in anti-tumor immunotherapy protocols. Full article

(This article belongs to the Special Issue Natural Killer Cells in Cancer Biology and Therapy)

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