Immunomodulation in cancer therapeutics

Ehrke, M. Jane

doi:10.1016/s1567-5769(03)00021-3

Cited by 92 publications

(64 citation statements)

References 52 publications

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“…on May 10, 2018. by guest www.bloodjournal.org From evidence demonstrating that exposure to low-dose chemotherapeutics is able to increase immune responses, including NK-cell activity, whereas high doses of the same agents are immunosuppressive. 49 In this regard, in older patients affected by MM, administration of intermediate doses of melphalan increases response rate and improves remission duration and survival, and we can envisage that its action might also be attributable to an induction of innate immune responses. 50 Induction of cellular senescence by chemotherapeutic agents has emerged as a primary mechanism of tumor regression through its antiproliferative power.…”

Section: Discussionmentioning

confidence: 99%

ATM-ATR–dependent up-regulation of DNAM-1 and NKG2D ligands on multiple myeloma cells by therapeutic agents results in enhanced NK-cell susceptibility and is associated with a senescent phenotype

Soriani

Zingoni

Cerboni

et al. 2009

Blood

386

416

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IntroductionNatural killer (NK) cells are present in the bloodstream, spleen, bone marrow, and in nonlymphoid organs and represent one of the main effectors of the immunosurveillance against tumors, by exerting 2 major effector functions, cytolysis of target cells and production of cytokines and chemokines. 1,2 The activity of NK cells depends on the interplay between inhibitory receptors for major histocompatibility complex (MHC) class I molecules and activating receptors, which operate in concert to induce the elimination of tumor cells. 3,4 Among the activating receptors particularly relevant for tumor cell recognition and killing is NKG2D, the receptor for the MHC I-related molecules MICA/B, and ULBPs (UL16-binding proteins), belonging to the C-type lectin-like receptor family. 3,[5][6][7] The NKG2D activating receptor is expressed not only on NK cells, but also on ␥␦ T cells, CD8 ϩ T cells, and a subset of CD4 ϩ T cells. The expression of NKG2D ligands is largely confined to virus-infected, tumor, and stressed cells. 7 To promote escape of tumors from NKG2D-mediated immunosurveillance, NKG2D ligands undergo proteolytic shedding. Soluble NKG2D ligands (NKG2DLs) have been shown to down-regulate the cell surface NKG2D expression on NK cells, resulting in impaired killing of tumor cells. 8,9 Another activating receptor involved in NK-cell-mediated tumor cell killing is DNAX accessory molecule-1 (DNAM-1), a transmembrane glycoprotein constitutively expressed on the majority of T cells, NK cells, and macrophages; its ligands are Nectin-2 (Nec-2, CD112) and the poliovirus receptor (PVR, CD155), which belong to the nectin/nectin-like family. 10-12 DNAM-1 ligands have been initially described as adhesion molecules mainly regulating trans-endothelial migration 13 and only recently they have been found on a variety of tumor cells. 12,14 Both DNAM-1 and NKG2D cooperate in the induction of NK-cell killing against tumor cells of different histotypes, including those of hematopoietic origin. 14,15 Similarly to the NKG2D ligands, soluble isoforms of PVR have also been found in human serum and in the culture supernatant of tumor cell lines, and their role in tumor immunoevasion has been considered. 12 It has recently been demonstrated that agents that produce a genotoxic stress or DNA-replication inhibitors up-regulate NKG2D ligand expression through the activation of ATM (ataxia telangiectasia mutated) and ATR (ATM-and Rad3-related) protein kinases on human fibroblasts and on mouse tumor cell lines, and enhance their destruction by NK cells. 16,17 Increased ligand expression is regulated by the activation of the DNA damage response (DDR). This is a cellular program devoted to the maintenance of genome integrity through the inhibition of cell cycle and activation of the DNA repair systems, or by the induction of apoptosis or a protracted cell-cycle arrest known as cellular senescence. 17,18 No information is so far available on the regulation of DNAM-1 ligand expression through the DDR pathway.Submitted August 11, 2008; acc...

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Section: Discussionmentioning

confidence: 99%

ATM-ATR–dependent up-regulation of DNAM-1 and NKG2D ligands on multiple myeloma cells by therapeutic agents results in enhanced NK-cell susceptibility and is associated with a senescent phenotype

Soriani

Zingoni

Cerboni

et al. 2009

Blood

386

416

View full text Add to dashboard Cite

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“…One or two injections of doxorubicin at moderate doses increase the activity of macrophages, natural killer (NK) cells, lymphokine-activated killer (LAK) cells, and CTLs and increase the production of interleukin-2 (IL-2) both in mice and in humans (7)(8)(9)(10).…”

Section: Introductionmentioning

confidence: 99%

“…The IL-2 is likely to function to maintain the immune response initiated as a consequence of doxorubicin administration, but IL-2 itself apparently does not induce, or does not induce effectively enough, the initial immune response events. IL-2 is given clinically at very high doses for a short period of time (9,12). Under these regimens, known for their toxicity, IL-2 is thought to provide all the stimulation for an anticancer immune response.…”

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confidence: 99%

Doxorubicin plus Interleukin-2 Chemoimmunotherapy against Breast Cancer in Mice

et al. 2006

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As recently characterized, following s.c. implantation into syngeneic C57BL/6 mice, E0771 tumor invades locally into dermal layers and peritoneum, metastasizes to the lung, and induces a nonspecific immunosuppression in the host. Using this breast medullar adenocarcinoma model, a therapy consisting of a single moderate dose of doxorubicin followed by twice daily moderate doses of interleukin-2 for 30 days was examined for efficacy and mechanism of action when given to animals with established disease. This combination treatment, but not combinants alone, resulted in tumor-free long-term survival of 40% of the mice without significant toxicity and 83% of survivors had immune memory specific for E0771 cells. Treatment also decreased immune suppression induced by E0771 tumor. Full response to treatment required functional CD8 + T cells, whereas depletion of natural killer cells caused only a reduction in response rate. A serum ''biomarker'' profile that correlated with, and seemed predictive of, response to treatment was identified by nuclear magnetic resonance-based metabonomic analysis. The efficacy of this nontoxic treatment and the potential to be able to predict which individual is responding to treatment are characteristics that make this chemoimmunotherapy attractive for clinical testing.

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“…It is plausible, however, that part of their efficacy stems from enhanced NK or T cell-mediated rejection of the cells due to activation of the DNA damage response in vivo. In several experimental tumor models, low doses of chemotherapeutics were shown to greatly enhance host antitumor immunity (35,36). Moreover, a number of studies suggest that low dose treatment with chemotherapeutics is sometimes equal or even superior to high-dose chemotherapy, which is often immunosuppressive (37).…”

Section: Dna Damage Response: a Link To Nkg2d Ligand Expression In Tumentioning

confidence: 99%

The DNA Damage Response Arouses the Immune System

2006

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Although there is considerable knowledge of how DNA damage triggers cell cycle arrest, DNA repair, and apoptosis, little was known about its potential role in immune responses. Recently, we showed that genotoxic stress and stalled DNA replication forks induce the expression of ligands for the NKG2D receptor found in natural killer cells and certain T cells, cell types that are able to attack tumor cells. Chronic activation of this response in tumor cells may contribute to immune recognition, but it also imposes a selection mechanism for immune escape and malignant progression. This unique arm of the DNA damage response may have implications for understanding therapeutic responses, many of which induce the DNA damage response, and for designing more effective regimens to treat cancer. (Cancer Res 2006; 66(8): 3959-62)

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Immunomodulation in cancer therapeutics

Cited by 92 publications

References 52 publications

ATM-ATR–dependent up-regulation of DNAM-1 and NKG2D ligands on multiple myeloma cells by therapeutic agents results in enhanced NK-cell susceptibility and is associated with a senescent phenotype

ATM-ATR–dependent up-regulation of DNAM-1 and NKG2D ligands on multiple myeloma cells by therapeutic agents results in enhanced NK-cell susceptibility and is associated with a senescent phenotype

Doxorubicin plus Interleukin-2 Chemoimmunotherapy against Breast Cancer in Mice

The DNA Damage Response Arouses the Immune System

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