Challenges of NK cell-based immunotherapy in the new era

Fang, Fang; Xiao, Weihua; Tian, Zhigang

doi:10.1007/s11684-018-0653-9

Cited by 36 publications

(30 citation statements)

References 132 publications

(100 reference statements)

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“…However, these approaches are undesirable to treat patients with solid tumors. The safety of adoptive transfer of autologous or allogeneic NK cells has been proved; however, efficacy is limited by their poor proliferation and persistence in vivo and the increase in Tregs related to IL-2 administration (53). Administration of exogenous IL-15 has been shown to improve survival, in vivo persistence, and therapeutic efficacy without inducing the survival and expansion of Tregs (54,55).…”

Section: Cytokine-activated Nk Cells In Tumor Immunotherapymentioning

confidence: 99%

Targeting Natural Killer Cells for Tumor Immunotherapy

Zhang

Shi

2020

Front. Immunol.

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Natural killer (NK) cells are important innate cytotoxic lymphocytes with a rapid and efficient capacity to recognize and kill tumor cells. In recent years, adoptive transfer of autologous-or allogeneic-activated NK cells has become a promising cellular therapy for cancer. However, the therapeutic efficiency is encouraging in hematopoietic malignancies, but disappointing in solid tumors, for which the use of NK-cell-based therapies presents considerable challenges. It is difficult for NK cells to traffic to, and infiltrate into, tumor sites. NK cell function, phenotype, activation, and persistence are impaired by the tumor microenvironment, even leading to NK cell dysfunction or exhaustion. Many strategies focusing on improving NK cells' durable persistence, activation, and cytolytic activity, including activation with cytokines or analogs, have been attempted. Modifying them with chimeric antigen receptors further increases the targeting specificity of NK cells. Checkpoint blockades can relieve the exhausted state of NK cells. In this review, we discuss how the cytolytic and effector functions of NK cells are affected by the tumor microenvironment and summarize the various immunotherapeutic strategies based on NK cells. In particular, we discuss recent advances in overcoming the suppressive effect of the tumor microenvironment with the aim of enhancing the clinical outcome in solid tumors treated with NK-cell-based immunotherapy.

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Section: Cytokine-activated Nk Cells In Tumor Immunotherapymentioning

confidence: 99%

Targeting Natural Killer Cells for Tumor Immunotherapy

Zhang

Shi

2020

Front. Immunol.

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“…Other cytokines, such as IL-7, IL-18, and IL-21 had positive results in preclinical studies [32,41].…”

Section: In Vivo Effects Of Cytokinesmentioning

confidence: 99%

Natural Killer Cell-Mediated Cellular Therapy of Hematological Malignancies

Şahin¹,

Beksaç²

2019

CHI

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A B S T R A C TOur understanding on the mechanisms of graft versus tumor/leukemia (GvT/GvL) and graft versus host (GvH) effects has tremendously evolved within the past decades. During the search for a mechanism that augments GvT/GvL without increasing GvH effects, natural killer (NK) cells have clearly attracted attention. Current approaches of NK cell immunotherapy for hematological malignancies involve using methods for in vivo potentiation of NK cell proliferation and activity; adoptive transfer of NK cells from autologous and allogeneic sources [cord blood mononuclear cells, peripheral blood mononuclear cells, CD34 + stem cells] and NK cell lines; and genetic modification of NK cells. Several cytokines, including interleukin-2 and interleukin-15 take part in the development of NK cells and have been shown to boost NK cell effects both in vivo and ex vivo. Monoclonal antibodies directed towards certain targets, including stimulating CD16, blockade of NK cell receptors, and redirection of cytotoxicity to tumor cells via bi-or tri-specific engagers may promote NK cell function. Despite the relative disappointment with autologous NK cell infusions, the future holds promise in adoptive transfer of allogeneic NK cells and the development of novel cellular therapeutic strategies, such as chimeric antigen receptor-modified NK cell immunotherapy. In this review, we summarize the current status of NK cell-related mechanisms in the therapy of hematologic malignancies, and discuss the future perspectives on adoptive NK cell transfer and other novel cellular immunotherapeutic strategies.

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“…6 Natural killer (NK) cells are essential lymphocytes that can kill virus-infected and cancer cells. [7][8][9] NK cells perform crucial functions during early HCC development. NK cells are defined as CD3 − CD56 + cells in humans and as CD3 − NK1.1 + or CD3 − NKp46 + cells in mice.…”

Section: Introductionmentioning

confidence: 99%

EpCAM-high liver cancer stem cells resist natural killer cell–mediated cytotoxicity by upregulating CEACAM1

Park

Sung

Kim

et al. 2020

J Immunother Cancer

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BackgroundNatural killer (NK) cells can recognize and kill cancer cells directly, but their activity can be attenuated by various inhibitory molecules expressed on the surface. The expression of epithelial cell adhesion molecule (EpCAM), a potential marker for cancer stem cells (CSCs), is known to be strongly associated with poor clinical outcomes in hepatocellular carcinoma (HCC). NK cells targeting CSCs may be a promising strategy for anti-tumor therapy, but little is known about how they respond to EpCAMhighCSCs in HCC.MethodsEpCAM expression was assessed by immunohistochemistry in 280 human HCC tissues obtained from curative surgery. To investigate the functional activity of NK cells against liver CSCs, EpCAMhighand EpCAMlowHuh-7 cells were sorted by flow cytometry. The functional role of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), which is related to NK cells, was determined by in vitro co-culture of NK cells and hepatoma cells using Hepa1–6 mouse hepatoma cells, as well as in vivo experiments using C57/BL6 mice.ResultsThe frequency of recurrence after curative surgery was higher in patients with positive EpCAM expression than in those with negative EpCAM expression. In subsequent analysis based on the anatomical location of EpCAM expression, patients with peritumoral EpCAM expression showed worse prognosis than those with pantumoral EpCAM expression. Co-culture experiments demonstrated that CEACAM1 was upregulated on the surface of EpCAMhighHCC cells, resulting in resistance to NK cell-mediated cytotoxicity. Inversely, silencing CEACAM1 restored cytotoxicity of NK cells against EpCAMhighHuh-7 cells. Moreover, neutralizing CEACAM1 on the NK cell surface enhanced killing of Huh-7 cells, suggesting that homophilic interaction of CEACAM1 is responsible for attenuated NK cell–mediated killing of CEACAM1highcells. In mouse experiments with Hepa1–6 cells, EpCAMhighHepa1–6 cells formed larger tumors and showed higher CEACAM1 expression after NK cell depletion. NK-mediated cytotoxicity was enhanced after blocking CEACAM1 expression using the anti-CEACAM1 antibody, thereby facilitating tumor regression. Moreover, CEACAM1 expression positively correlated with EpCAM expression in human HCC tissues, and serum CEACAM1 levels were also significantly higher in patients with EpCAM+HCC.ConclusionOur data demonstrated that EpCAMhighliver CSCs resist NK cell–mediated cytotoxicity by upregulation of CEACAM1 expression.

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Challenges of NK cell-based immunotherapy in the new era

Cited by 36 publications

References 132 publications

Targeting Natural Killer Cells for Tumor Immunotherapy

Targeting Natural Killer Cells for Tumor Immunotherapy

Natural Killer Cell-Mediated Cellular Therapy of Hematological Malignancies

EpCAM-high liver cancer stem cells resist natural killer cell–mediated cytotoxicity by upregulating CEACAM1

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