Necrotic Tumor Cell Death In Vivo Impairs Tumor-Specific Immune Responses

Gamrekelashvili, Jaba; Krüger, Caroline; Wasielewski, Reinhard von; Hoffmann, Matthias; Huster, Katharina M.; Busch, Dirk H.; Manns, Michael P.; Korangy, Firouzeh; Greten, Tim F.

doi:10.4049/jimmunol.178.3.1573

Cited by 43 publications

(36 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…90 HMGB1 release has been considered as a potential way of inducing an immune response against dying tumor cells undergoing necrosis. However, several studies showed that necrotic cells were unable to trigger an immune response 91,92 when injected in vivo, in contrast to the initial expectations. Recently, it has been found that tumor cells that undergo apoptosis in vitro, in response to anthracyclines, could mediate a potent antitumor vaccination effect when they were injected subcutaneously into syngeneic immunogenic mice.…”

mentioning

confidence: 40%

Molecular characteristics of immunogenic cancer cell death

et al. 2007

View full text Add to dashboard Cite

Apoptotic cell death is initiated by a morphologically homogenous entity that was considered to be non-immunogenic and noninflammatory in nature. However, recent advances suggest that apoptosis, under certain circumstances, can be immunogenic. In particular, some characteristics of the plasma membrane, acquired at preapoptotic stage, can cause immune effectors to recognize and attack preapoptotic tumor cells. The signals that mediate the immunogenicity of tumor cells involve elements of the DNA damage response (such as ataxia telangiectasia mutated and p53 activation), elements of the endoplasmic reticulum stress response (such as eukaryotic initiation factor 2a phosphorylation), as well as elements of the apoptotic response (such as caspase activation). Depending on the signal-transduction pathway, tumor cells responding to chemotherapy or radiotherapy can express 'danger' and 'eat me' signals on the cell surface (such as NKG2D ligands, heat-shock proteins and calreticulin) or can secrete/release immunostimulatory factors (such as cytokines and high-mobility group box 1) to stimulate innate immune effectors. Likewise, the precise sequence of such events influences the 'decision' of the immune system to mount a cognate response or not. We therefore anticipate that the comprehension of the mechanisms governing the immunogenicity of cell death will have a profound impact on the design of anticancer therapies.

show abstract

mentioning

confidence: 40%

Molecular characteristics of immunogenic cancer cell death

et al. 2007

View full text Add to dashboard Cite

show abstract

“…In addition, Ullman et al (18) reported that autophagy activates necrosis in apoptosis-deficient mouse embryonic fibroblasts. Gamrekelashvili et al (19) reported that necrosis may inhibit cancer recurrence by acquiring tolerance without inducing tumor immunity such as apoptosis. In our study, DHL-TauZnNa showed an antiproliferative effect associated with autophagy in HT-29 cells, which exhibit resistance to apoptosis and chemoresistance (20), suggesting that DHL-TauZnNa may be a new therapeutic strategy against cancer cells with resistance to apoptosis.…”

Section: Discussionmentioning

confidence: 99%

DHL-TauZnNa, a newly synthesized α-lipoic acid derivative, induces autophagy in human colorectal cancer cells

et al. 2013

View full text Add to dashboard Cite

Abstract. In recent years, several antioxidant substances have been found to have an antiproliferative effect on various types of carcinomas. α-lipoic acid (ALA) induces apoptosis in several types of cancer cell lines, but it is difficult to apply α-lipoic acid in clinical use as it is easily oxidized and unstable. Recently, we succeeded in synthesizing the α-lipoic acid derivative sodium N-[6,8-dimercaptooctanoyl]-2-aminoethanesulfonate zinc complex (DHL-TauZnNa), which has highly stable antioxidant effects. We investigated whether DHL-TauZnNa elicits its antiproliferative effects in vivo and in vitro by inducing apoptosis, autophagy or cell cycle arrest, and we analyzed the expression of proteins related to these phenomena and their phosphorylation in HT-29 human colon cancer cells. Subcutaneously administered DHL-TauZnNa treatment applied daily for 41 days significantly inhibited tumor growth by 43% in a xenograft mouse model (P=0.0271). DHL-TauZnNa significantly reduced cell viability over that of controls in the trypan-blue exclusion test in a time-and dose-dependent manner (P<0.05). DHL-TauZnNa increased the proportion of cells in S phase and decreased that of cells in G0/G1 phase in the cell cycle analysis of HT-29 cells. Although DHL-TauZnNa did not increase caspase-3/7 activity and DNA fragmentation in flow cytometry analysis, it increased the expression of microtubule-associated protein light chain 3-II. Autophagosomes and autolysosomes were observed by electron microscopy in the cytoplasm of HT-29 cells treated with DHL-TauZnNa. These results suggest that DHL-TauZnNa inhibited the proliferation of HT-29 cells through the mechanisms of G2/M cell cycle arrest and autophagy but not that of apoptosis. The newly synthesized ALA derivative DHL-TauZnNa may be expected to become a novel cancer therapeutic strategy through its induction of autophagy.

show abstract

“…However the distinction between apoptosis and necrosis as immunogenic or nonimmunogenic forms of cell death respectively, may be too simplistic. Recent studies have shown that apoptotic death of tumor cells by certain agents (such as anthracyclines, proteasome inhibitors, or viral infection) can be immunogenic [16][17][18][19], while necrotic cell death may impair tumor immunity in vivo [20]. Moreover destroying the anthracycline induced apoptotic bodies by freeze thaw abolished their immunogenicity [18].…”

Section: Exposure Of Hsps During Cell Deathmentioning

confidence: 99%

Role of chaperones and FcγR in immunogenic death

Dhodapkar

2008

Current Opinion in Immunology

View full text Add to dashboard Cite

Cell death under physiologic conditions does not lead to the induction of immunity. However recognition of stressed or opsonized cells can trigger immune responses. Recent studies have begun to illustrate the critical role of molecular chaperones such as inducible heat shock proteins in mediating immunogenicity of stressed cells. Immunity to opsonized cells depends in part on the engagement and the balance of activating and inhibitory FcγRs on antigen presenting dendritic cells. Understanding both these pathways of immunogenic cell death may yield novel approaches to regulate immunity. Two forms of immunogenic cell deathBillions of cells die each day and are replaced by newly differentiated progeny. Corpses of such dying cells are rapidly removed by phagocytes; do not elicit immunity and may induce tolerance. However under some settings, recognition of dying cells leads to inflammatory responses and immunity[1] • . Two aspects of such "immunogenic death" are the focus of this review. A common response to cellular stress is the transcriptional activation of molecular chaperones that belong to the class of inducible heat shock proteins (HSPs). Another setting wherein dying cells might induce immunity is when they are opsonized by antibodies due to antibody mediated recognition of determinants on dying cells. Such opsonized cells can be recognized by FcγR mediated pathways on antigen presenting cells (APCs). Below, we will discuss recent insights into how both of these pathways play an important role in regulating immunogenicity of dying cells and can be dysregulated in autoimmunity. Heat shock proteins (HSPs) and immunogenic cell deathHSPs are referred to as stress proteins or molecular chaperones, although most HSPs are constitutively expressed. Known best for their roles in regulating intracellular protein homeostasis, HSPs were immunologically implicated because of the observations that tumor-derived HSPs, although having no tumor-specific mutations, can immunize for tumor-specific T cell immunity [2] • . Efforts to explain the phenomenon have led to two

show abstract

Necrotic Tumor Cell Death In Vivo Impairs Tumor-Specific Immune Responses

Cited by 43 publications

References 46 publications

Molecular characteristics of immunogenic cancer cell death

Molecular characteristics of immunogenic cancer cell death

DHL-TauZnNa, a newly synthesized α-lipoic acid derivative, induces autophagy in human colorectal cancer cells

Role of chaperones and FcγR in immunogenic death

Contact Info

Product

Resources

About