Role of immune cells in the removal of deleterious senescent cells

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Abstract

Cellular senescence is an essentially irreversible arrest of cell proliferation coupled to a complex senescence-associated secretory phenotype (SASP). The senescence arrest prevents the development of cancer, and the SASP can promote tissue repair. Recent data suggest that the prolonged presence of senescent cells, and especially the SASP, could be deleterious, and their beneficial effects early in life can become maladaptive such that they drive aging phenotypes and pathologies late in life. It is therefore important to develop strategies to eliminate senescent cells. There are currently under development or approved several immune cell-based therapies for cancer, which could be redesigned to target senescent cells. This review focuses on this possible use of immune cells and discusses how current cell-based therapies could be used for senescent cell removal.

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Aging, Cellular Senescence, and Cancer

Judith Campisi (2013)

For most species, aging promotes a host of degenerative pathologies that are characterized by debilitating losses of tissue or cellular function. However, especially among vertebrates, aging also promotes hyperplastic pathologies, the most deadly of which is cancer. In contrast to the loss of function that characterizes degenerating cells and tissues, malignant (cancerous) cells must acquire new (albeit aberrant) functions that allow them to develop into a lethal tumor. This review discusses the idea that, despite seemingly opposite characteristics, the degenerative and hyperplastic pathologies of aging are at least partly linked by a common biological phenomenon: a cellular stress response known as cellular senescence. The senescence response is widely recognized as a potent tumor suppressive mechanism. However, recent evidence strengthens the idea that it also drives both degenerative and hyperplastic pathologies, most likely by promoting chronic inflammation. Thus, the senescence response may be the result of antagonistically pleiotropic gene action.

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Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas.

Wen Xue, Lars Zender, Cornelius Miething … (2007)

Although cancer arises from a combination of mutations in oncogenes and tumour suppressor genes, the extent to which tumour suppressor gene loss is required for maintaining established tumours is poorly understood. p53 is an important tumour suppressor that acts to restrict proliferation in response to DNA damage or deregulation of mitogenic oncogenes, by leading to the induction of various cell cycle checkpoints, apoptosis or cellular senescence. Consequently, p53 mutations increase cell proliferation and survival, and in some settings promote genomic instability and resistance to certain chemotherapies. To determine the consequences of reactivating the p53 pathway in tumours, we used RNA interference (RNAi) to conditionally regulate endogenous p53 expression in a mosaic mouse model of liver carcinoma. We show that even brief reactivation of endogenous p53 in p53-deficient tumours can produce complete tumour regressions. The primary response to p53 was not apoptosis, but instead involved the induction of a cellular senescence program that was associated with differentiation and the upregulation of inflammatory cytokines. This program, although producing only cell cycle arrest in vitro, also triggered an innate immune response that targeted the tumour cells in vivo, thereby contributing to tumour clearance. Our study indicates that p53 loss can be required for the maintenance of aggressive carcinomas, and illustrates how the cellular senescence program can act together with the innate immune system to potently limit tumour growth.

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Nitric oxide and macrophage function.

John MacMicking, Qiao-wen Xie, Carl Nathan (1997)

At the interface between the innate and adaptive immune systems lies the high-output isoform of nitric oxide synthase (NOS2 or iNOS). This remarkable molecular machine requires at least 17 binding reactions to assemble a functional dimer. Sustained catalysis results from the ability of NOS2 to attach calmodulin without dependence on elevated Ca2+. Expression of NOS2 in macrophages is controlled by cytokines and microbial products, primarily by transcriptional induction. NOS2 has been documented in macrophages from human, horse, cow, goat, sheep, rat, mouse, and chicken. Human NOS2 is most readily observed in monocytes or macrophages from patients with infectious or inflammatory diseases. Sustained production of NO endows macrophages with cytostatic or cytotoxic activity against viruses, bacteria, fungi, protozoa, helminths, and tumor cells. The antimicrobial and cytotoxic actions of NO are enhanced by other macrophage products such as acid, glutathione, cysteine, hydrogen peroxide, or superoxide. Although the high-output NO pathway probably evolved to protect the host from infection, suppressive effects on lymphocyte proliferation and damage to other normal host cells confer upon NOS2 the same protective/destructive duality inherent in every other major component of the immune response.

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Author and article information

Contributors

Judith Campisi: jcampisi@lbl.gov , jcampisi@buckinstitute.org

Journal

Journal ID (nlm-ta): Immun Ageing

Journal ID (iso-abbrev): Immun Ageing

Title: Immunity & Ageing : I & A

Publisher: BioMed Central (London )

ISSN (Electronic): 1742-4933

Publication date (Electronic): 3 June 2020

Publication date PMC-release: 3 June 2020

Publication date Collection: 2020

Volume: 17

Electronic Location Identifier: 16

Affiliations

[1 ]GRID grid.272799.0, ISNI 0000 0000 8687 5377, Buck Institute for Research on Aging, ; 8001 Redwood Boulevard, Novato, CA 94945 USA

[2 ]SENS Research Foundation, 110 Pioneer Way, Suite J, Mountain View, CA 94041 USA

[3 ]GRID grid.6571.5, ISNI 0000 0004 1936 8542, Centre for Biological Engineering, Wolfson School of Mechanical, Electrical and Manufacturing Engineering, , Loughborough University, ; Loughborough, UK

[4 ]GRID grid.17866.3e, ISNI 0000000098234542, California Pacific Medical Center, Research Institute, ; San Francisco, CA 94107 USA

[5 ]GRID grid.184769.5, ISNI 0000 0001 2231 4551, Biosciences Division, , Lawrence Berkeley National Laboratory, ; Berkeley, CA 94720 USA

Article

Publisher ID: 187

DOI: 10.1186/s12979-020-00187-9

PMC ID: 7271494

PubMed ID: 32518575

SO-VID: 7cf081d8-284d-4b0e-a84f-885306026f92

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 16 February 2020

Date accepted : 18 May 2020

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100013772, SENS Research Foundation;

Award ID: NA

Award Recipient : Judith Campisi

Custom metadata

ScienceOpen disciplines: Immunology

Keywords: age-related pathology,cell-based therapy,cellular senescence,immune surveillance,inflammation,macrophages,natural killer cells

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ScienceOpen disciplines: Immunology

Keywords: age-related pathology, cell-based therapy, cellular senescence, immune surveillance, inflammation, macrophages, natural killer cells

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Role of immune cells in the removal of deleterious senescent cells

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Most cited references 73

Aging, Cellular Senescence, and Cancer

Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas.

Nitric oxide and macrophage function.

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