The Emergence of Natural Killer Cells as a Major Target in Cancer Immunotherapy

Souza-Fonseca-Guimarães, Fernando; Cursons, Joseph; Huntington, Nicholas D.

doi:10.1016/j.it.2018.12.003

Cited by 229 publications

(202 citation statements)

References 106 publications

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“…Recent studies demonstrate that it is the NK cells that are predominantly responsible for restricting tumor metastasis, mainly by three MHC‐mediated antigen presentation independent ways: ( i ) perforin and granzyme B granules release; ( ii ) interferon‐γ secretion; and ( iii ) death receptor ligands exposure . Although the activation of NK cells depends on the balance of signaling between activating receptors and inhibitory receptors, numerous cytokines were also reported to regulate NK cell function: IL‐15 is essential for NK survival and function; IL‐12 is a critical to drive NK cell cytokine production (like IFN‐γ and GM‐CSF); IL‐18 is important for NK cell priming and IL‐12‐induced IFN‐γ production . However, the regulation of NK cell function in TME remains much unknown.…”

Section: Introductionmentioning

confidence: 99%

“…7 Although the activation of NK cells depends on the balance of signaling between activating receptors and inhibitory receptors, numerous cytokines were also reported to regulate NK cell function: IL-15 is essential for NK survival and function; IL-12 is a critical to drive NK cell cytokine production (like IFN-γ and GM-CSF); IL-18 is important for NK cell priming and IL-12-induced IFN-γ production. 8 However, the regulation of NK cell function in TME remains much unknown.…”

Section: Introductionmentioning

confidence: 99%

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Interleukin‐33 activates and recruits natural killer cells to inhibit pulmonary metastatic cancer development

Zhang

Miao

et al. 2019

Intl Journal of Cancer

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Increasing evidence suggests that IL‐33 plays an important role in regulating tumor development. However, conflicting results, obtained from numerous studies, have highlighted the divergent functions of IL‐33. The detailed mechanisms by which IL‐33 modulates tumor development merit further investigation. Here, we report that IL‐33 administration can effectively inhibit the development of pulmonary metastasis of breast cancer in a mouse. In our model, IL‐33 promotes the production of TNF‐α by macrophages, which increases IL‐33 specific receptor (ST2) expression on natural killer (NK) cells and is pivotal in IL‐33‐induced NK cell activation. IL‐33 treatment also facilitates the production of CCL5 in the lung by eosinophils and CD8+ T cells, which mediates the recruitment of NK cells to the tumor microenvironment. The systemic activation and local recruitment of NK cells result in potent tumor rejection in the lung. Our study reports a novel mechanism for the IL‐33‐meditated suppression of metastatic cancer and provides potential therapeutic strategies for targeting metastatic tumor.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Interleukin‐33 activates and recruits natural killer cells to inhibit pulmonary metastatic cancer development

Zhang

Miao

et al. 2019

Intl Journal of Cancer

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“…Growing evidence for the role of NK cells in cancer immune surveillance and clearance has included human data demonstrating that patients with high intratumoral NK cell frequency have significantly improved survival outcomes . Thus, it is not surprising that NK cells have become a high priority in immunotherapy development …”

Section: Introductionmentioning

confidence: 99%

Quantifying NK cell growth and survival changes in response to cytokines and regulatory checkpoint blockade helps identify optimal culture and expansion conditions

Hennessy

Pham

Delconte

et al. 2019

Journal of Leukocyte Biology

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NK cells are innate lymphocytes critical for immune surveillance, particularly in eradication of metastatic cancer cells and acute antiviral responses. In contrast to T cells, NK cell‐mediated immunity is rapid, with spontaneous cytotoxicity and cytokine/chemokine production upon pathogen detection. The renaissance in cancer immunology has cast NK cell biology back into the spotlight with an urgent need for deeper understanding of the regulatory networks that govern NK cell antitumor activity. To this end, we have adapted and refined a series of quantitative cellular calculus methods, previously applied to T and B lymphocytes, to dissect the biologic outcomes of NK cells following stimulation with cytokines (IL‐15, IL‐12, IL‐18) or deletion of genes that regulate NK cell proliferation (Cish), survival (Bcl2l11), and activation‐induced‐cell‐death (AICD; Fas). Our methodology is well suited to delineate effects on division rate, intrinsic apoptosis, and AICD, permitting variables such as population half‐life, rate of cell division, and their combined influence on population numbers in response to stimuli to be accurately measured and modelled. Changes in these variables that result from gene deletion, concentration of stimuli, time, and cell density give insight into the dynamics of NK cell responses and serve as a platform to dissect the mechanism of action of putative checkpoints in NK cell activation and novel NK cell immunotherapy agents.

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“…Melanoma has been recognized as one of the most immunogenic malignancies with abundant infiltration of various immune cells . NK cells, T helper type 1 cells and cytotoxic CD8 + T cells constitute the major anti‐tumor immunity, but tumor‐infiltrating myeloid cells, including macrophages and myeloid‐derived suppressor cells (MDSCs) and Foxp3 + regulatory T cells, suppress anti‐tumor immunity . Hence, tumor progression is influenced by the balance between pro‐tumor immunosuppression and anti‐tumor immunity.…”

Section: Introductionmentioning

confidence: 99%

“…17 NK cells, T helper type 1 cells and cytotoxic CD8 + T cells constitute the major anti-tumor immunity, but tumor-infiltrating myeloid cells, including macrophages and myeloid-derived suppressor cells (MDSCs) and Foxp3 + regulatory T cells, suppress anti-tumor immunity. [18][19][20] Hence, tumor progression is influenced by the balance between pro-tumor immunosuppression and anti-tumor immunity. Pachynski et al 12 have reported that overexpression of chemerin in murine melanoma B16F10 cells is able to inhibit melanoma growth by recruitment of NK cells in a CMKLR1-dependent way.…”

Section: Introductionmentioning

confidence: 99%

Chemerin partly mediates tumor‐inhibitory effect of all‐trans retinoic acid via CMKLR1‐dependent natural killer cell recruitment

et al. 2019

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Summary Down‐regulated chemerin expression has been reported to correlate with poor prognosis of several types of cancer including melanoma. All‐trans retinoic acid (atRA) is a potent inducer of chemerin, and we previously reported that atRA inhibited murine melanoma growth through enhancement of anti‐tumor T‐cell immunity. Here, we aimed to investigate whether loss of endogenous chemerin accelerated melanoma growth and whether chemerin was involved in the melanoma‐inhibitory effect of atRA. We demonstrated that chemerin was constitutively expressed in the skin, which was down‐regulated during murine melanoma growth. Rarres2−/− mice, which are deficient in chemerin, exhibited aggravated tumor growth and impaired tumor‐infiltrating natural killer (NK) cells that express CMKLR1, the functional receptor of chemerin. Topical treatment with atRA up‐regulated skin chemerin expression, which was primarily derived from dermal cells. Moreover, atRA treatment significantly enhanced tumor‐infiltrating NK cells, which was completely abrogated in Rarres2−/− mice and Cmklr1−/− mice, suggesting a dependency of NK cell recruitment on the chemerin–CMKLR1 axis in melanoma. Despite comparable melanoma growth detected in wild‐type mice and Cmklr1−/− mice, lack of CMKLR1 partially abrogated the melanoma‐inhibitory effect of atRA. This may be due to the inability to enhance tumor‐infiltrating NK cells in Cmklr1−/− mice following atRA treatment. Collectively, our study suggests that down‐regulation of chemerin could be a strategy used by cancers such as melanoma to impair anti‐tumor NK cell immunity and identifies a new anti‐tumor mechanism of atRA by up‐regulating chemerin to enhance CMKLR1‐dependent NK cell recruitment.

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The Emergence of Natural Killer Cells as a Major Target in Cancer Immunotherapy

Cited by 229 publications

References 106 publications

Interleukin‐33 activates and recruits natural killer cells to inhibit pulmonary metastatic cancer development

Interleukin‐33 activates and recruits natural killer cells to inhibit pulmonary metastatic cancer development

Quantifying NK cell growth and survival changes in response to cytokines and regulatory checkpoint blockade helps identify optimal culture and expansion conditions

Chemerin partly mediates tumor‐inhibitory effect of all‐trans retinoic acid via CMKLR1‐dependent natural killer cell recruitment

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