The DNA damage response, immunity and cancer

doi:10.1016/j.semcancer.2006.07.004

Seminars in Cancer Biology

Volume 16, Issue 5, October 2006, Pages 344-347

https://doi.org/10.1016/j.semcancer.2006.07.004 Get rights and content

Abstract

The genome is constantly exposed to exogenous DNA damaging events in the form of radiation, viral infection and chemicals. Endogenous processes such as DNA replication and free radical formation also threaten the integrity of the genome. DNA damage is directly deleterious to cells and also promotes tumorigenesis. Eukaryotic organisms have evolved a signaling pathway, called the DNA damage response, to protect against genomic insults. Sensor proteins detect various forms of damage, and convey signals via a complex pathway regulated by protein phosphorylation, stabilization and transcriptional regulation. The DNA damage response causes cell cycle arrest and induction of DNA repair functions, such that cells with modest damage may survive. However, cells with more severe damage are induced to undergo apoptosis. Two compelling studies show that the DNA damage response is activated very early during tumorigenesis, providing evidence that the DNA damage response could function as a barrier in early tumorigenesis. We recently demonstrated that the DNA damage response alerts the immune system by inducing expression of cell surface ligands for the activating immune receptor NKG2D, which is expressed by natural killer cells (NK cells) and some T cells. In this review we discuss the DNA damage response and its link to the innate immune system and tumor surveillance. These findings might have important implications for the understanding of cancer therapies and for drug development.

Section snippets

Surveillance against DNA damage

Maintenance of genome integrity after DNA damage is vital for eukaryotic cells. A failure can endanger the survival of the individual cell as well as of the organism. Following DNA damage, the PI3-kinase-relateded protein kinases ATM (Ataxia Telangiectasia, mutated) and ATR (ATM- and Rad3-Related) cooperate with other proteins to initiate the DNA damage response [4]. Double-strand breaks preferentially activate ATM, whereas stalled DNA replication induces ATR activity. In response to many

The DNA damage response induces expression of ligands for the NKG2D receptor

Direct evidence for such a role of the DNA damage response was provided by our finding that DNA damaging agents or DNA replication inhibitors, but not other common forms of stress, induce expression of cell surface protein ligands for the NKG2D receptor in an ATM or ATR dependent fashion [3]. NKG2D is an activating receptor expressed on NK cells, subsets of γ/δ T cells, NKT cells, and cytotoxic CD8⁺ T cells [7], [8], [9]. In humans, all CD8⁺ T cells express NKG2D. In contrast, NKG2D expression

Conclusion

We have recently shown that ligands for the activating immune receptor NKG2D are induced by the DNA damage response, which is activated early in tumorigenesis as well as during certain virus infections. Genotoxic stress may therefore represent an important means by which the immune system distinguishes diseased cells from normal cells. The resulting activation of the DNA damage response would allow a cell to recognize the “danger” posed by diseased cells and trigger signals that induce

Acknowledgments

We would like to thank the members of the Raulet laboratory for helpful discussions. This work was supported by grants from the National Institutes of Health to D.H. Raulet.

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Genotoxicity studies provide information on the effect of the drug into genetic material of healthy cells such as DNA modifications, base damage, sugar damage, and DNA-protein crosslinks. Such modifications can ultimately lead to single-strand and double-strands breaks, causing cell cycle arrest or promotion of tumorigenesis as well as initiation of immune response and inflammation [25]. In order to understand and predict the possible therapeutic effects of copper(II) complexes, it is necessary to examine and clarify the mechanisms of their action, especially the effect on cancer cells.
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Recently, with the clinical application of next-generation sequencing technologies, as a prominent poly [ADP-ribose] polymerase (PARP) involved in DNA repair, PARP1 has been demonstrated to be aberrant-expressed in SCLC and to participate in DNA damage repair, providing hope for the development of novel therapeutic targets for SCLC patients [6–10]. Within each cell cycle, DNA damage occurs, and cells have their own regulation repair systems to deal with it [11,12]. Tumor cells suffer more DNA damage than normal cells as a result of chemotherapy and radiation, and the DNA repair mechanism is unusually active [13].
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The immune landscape of a tumor is highly connected to patient prognosis and response to treatment, but little is known about how natural killer (NK) cells predict overall survival (OS) among patients with solid tumors. We present the first meta-analysis on NK cell infiltration into solid tumors as a prognostic indicator for OS, considering cancer types independently, and together. Samples were collected from 1973 to 2016 with results published between 1989 and 2020. From 53 studies, we found that NK cell infiltration corresponds with decreased risk of death (HR=0.34, 95% CI: 0.26–0.46; p<0.0001). Among studies that investigated the prognostic potential of NK cells in specific regions of the tumor, intraepithelial infiltration was better predictive of OS than NK infiltration in the tumor-adjacent stroma. Generally, NK cell infiltration is lower in advanced-stage and lower-grade tumors; nevertheless, it remains prognostically beneficial. This meta-analysis highlights an important prognostic role of NK cells in solid tumors, but exposes that few studies have considered the contributions of NK cells. Toward NK cell-based immunotherapies, it will be important to understand the conditions under which NK cells can be effective agents of tumor control.
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ReviewThe DNA damage response, immunity and cancer

Abstract

Section snippets

Surveillance against DNA damage

The DNA damage response induces expression of ligands for the NKG2D receptor

Conclusion

Acknowledgments

Mutat Res

Immunity

Immunity

Cell

DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis

Nature

Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions

Nature

The DNA damage pathway regulates innate immune system ligands of the NKG2D receptor

Nature

Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints

Annu Rev Biochem

DNA repair and cancer: lessons from mutant mouse models

Cancer Sci

Roles of the NKG2D immunoreceptor and its ligands

Nat Rev Immunol

Ligands for the murine NKG2D receptor: expression by tumor cells and activation of NK cells and macrophages

Nat Immunol

Review
The DNA damage response, immunity and cancer