Staphylococcal Superantigens of the Enterotoxin Gene Cluster (egc) for Treatment of Stage IIIb Non–Small Cell Lung Cancer with Pleural Effusion

Terman, David S.; Bohach, Gregory A.; Vandenesch, François; Étienne, Jérôme; Lina, Gérard; Sahn, Steven A.

doi:10.1016/j.ccm.2006.01.001

Cited by 13 publications

(11 citation statements)

References 83 publications

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“…This interaction results in polyclonal T-cell activation and massive secretion of cytokines such as interleukin-2 (IL)-2, interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), and nitric oxide (NO) (Marrack and Kappler, 1990). Several members of this group have been implicated in the pathogenesis of toxic shock syndrome and food poisoning, and have shown anti-tumor activity in animal models (Bohach, 2006; Terman et al, 2006). The egcSEs comprise five genetically linked staphylococcal enterotoxins, SEG, SEI, SElM, SElN and SElO and two pseudotoxins which constitute an operon present in up to 80% of S. aureus isolates (Jarraud et al, 2001; Becker et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Staphylococcal entertotoxins of the enterotoxin Gene cluster (egcSEs) induce nitrous oxide- and cytokine dependent tumor cell apoptosis in a broad panel of human tumor cells

Terman¹,

Serier²,

Dauwalder³

et al. 2013

Front. Cell. Infect. Microbiol.

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The egcSEs comprise five genetically linked staphylococcal enterotoxins, SEG, SEI, SElM, SElN, and SElO and two pseudotoxins which constitute an operon present in up to 80% of Staphylococcus aureus isolates. A preparation containing these proteins was recently used to treat advanced lung cancer with pleural effusion. We investigated the hypothesis that egcSEs induce nitric oxide (NO) and associated cytokine production and that these agents may be involved in tumoricidal effects against a broad panel of clinically relevant human tumor cells. Preliminary studies showed that egcSEs and SEA activated T cells (range: 11–25%) in a concentration dependent manner. Peripheral blood mononuclear cells (PBMCs) stimulated with equimolar quantities of egcSEs expressed NO synthase and generated robust levels of nitrite (range: 200–250 μM), a breakdown product of NO; this reaction was inhibited by NG-monomethyl-L-arginine (L-NMMA) (0.3 mM), an NO synthase antagonist. Cell free supernatants (CSFs) of all egcSE-stimulated PBMCs were also equally effective in inducing concentration dependent tumor cell apoptosis in a broad panel of human tumor cells. The latter effect was due in part to the generation of NO and TNF-α since it was significantly abolished by L-NMMA, anti-TNF-α antibodies, respectively, and a combination thereof. A hierarchy of tumor cell sensitivity to these CFSs was as follows: lung carcinoma > osteogenic sarcoma > melanoma > breast carcinoma >neuroblastoma. Notably, SEG induced robust activation of NO/TNFα-dependent tumor cell apoptosis comparable to the other egcSEs and SEA despite TNF-α and IFN-γ levels that were 2 and 8 fold lower, respectively, than the other egcSEs and SEA. Thus, egcSEs produced by S. aureus induce NO synthase and the increased NO formation together with TNF-α appear to contribute to egcSE-mediated apoptosis against a broad panel of human tumor cells.

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Section: Introductionmentioning

confidence: 99%

Staphylococcal entertotoxins of the enterotoxin Gene cluster (egcSEs) induce nitrous oxide- and cytokine dependent tumor cell apoptosis in a broad panel of human tumor cells

Terman¹,

Serier²,

Dauwalder³

et al. 2013

Front. Cell. Infect. Microbiol.

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“…The antitumor effects of Superantigen SEA are primarily related to the cytotoxicity of T-lymphocytes activated by SEA and the released cytokines by these T-lymphocytes [1,4,13]. In order to explore the mechanism of the inhibition of bladder cancer cell proliferation, we first measured the concentration of major cytokines such as IL-2, TNF-a, and IFN-c, released by SEA-stimulated T-cells in the co-culture supernatant.…”

Section: Discussionmentioning

confidence: 99%

“…Transurethral resection of bladder tumor is the standard treatment for this condition but it is feasible that cancer can recrudesce after operation [1]. Several evidences show that lymphocytes in the region of bladder tumor cannot be activated efficiently and thus these cells are unable to immune-surveillance the tumor, which causes immunological escape of tumor cells leading to tumor relapse.…”

mentioning

confidence: 99%

Mechanism of Monoclonal Antibody-Coupled Staphylococcus Superantigen-A Induced Apoptosis in Human Bladder Cancer Cells

Han

Gong

Hao

et al. 2011

Cell Biochem Biophys

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To investigate the mechanism of apoptosis induced by BDI-1 monoclonal antibody (MAb) coupled Staphylococcal superantigen-A (SEA) in human bladder cancer cell line BIU-87. Human PBMC (effector cells) mediated cytotoxic killing of BIU-87 cells (target cells) was studied by culturing the BIU-87 cells in the presence of effector cells plus medium after their activation by treatment with SEA-targeted by MAb, SEA alone or vehicle (control). Proliferation and apoptosis of BIU-87 cells was measured after the treatments. Expression of Bax and Bcl-2 and cytokine concentration in co-culture supernatants were detected by Western blot and ELISA, respectively. Proliferation of MAb-targeted SEA BIU-87 cells decreased significantly (P < 0.05) as compared to control and SEA groups. Flow cytometry revealed apoptosis in SEA alone and more prominently in targeted-SEA treated in BIU-87 cells, which is significantly more than in controI cells (P < 0.05). In addition, Western blot analysis indicated that the ratio of Bax/Bcl-2 significantly increased by targeted SEA treatment, even at low concentration, as compared to cells treated with SEA alone or control cells (P < 0.05). However, there were no significant differences in IL-2, TNF-α and IFN-γ levels in the culture medium between SEA and targeted SEA groups, even though they are several folds higher than in control cells. SEA targeting by MAb significantly increases apoptosis in BIU-87 cells, possibly through the up-regulation of proapoptotic protein Bax and down regulation of antiapoptotic protein, Bcl-2.

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“…In the current study, we replaced the first exon, first intron and part of the second exon of the beta‐globin transgene in the lentiviral vector with genes encoding several biologics including staphylococcal superantigens SEG/SEI and granzyme/perforin. The former are powerful T cell stimulants that have been implicated in anti‐tumor effects versus advanced non‐small cell lung cancer while the latter are the major cytotoxics used by T cells to generate tumor cytolytic effects . We hypothesized that the powerful β‐globin LCR and downstream promoter/enhancers would drive transcription of these genes.…”

Section: Introductionmentioning

confidence: 99%

Sickle cells produce functional immune modulators and cytotoxics

Sun

Knopick

et al. 2017

American J Hematol

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Sickle erythrocytes’ (SSRBCs) unique physical adaptation to hypoxic conditions renders them able to home to hypoxic tumor niches in vivo, shut down tumor blood flow and induce tumoricidal responses. SSRBCs are also useful vehicles for transport of encapsulated drugs and oncolytic virus into hypoxic tumors with enhanced anti-tumor effects. In search of additional modes for arming sickle cells with cytotoxics, we turned to a lentiviral β-globin vector with optimized Locus Control Region/β-globin coding region/promoter/enhancers. We partially replaced the β-globin coding region of this vector with genes from the T cell cytolytics, perforin and granzyme or immune modulating superantigens SEG and SEI. These modified vectors efficiently transduced Sca+ckit−Lin− HSCs from humanized sickle cell knockin mice. Irradiated mice reconstituted with these HSCs displayed robust expression of transgenic RNAs and proteins in host sickle cells that was sustained for more than 10 months. SSRBCs from reconstituted mice harboring SEG/SEI transgenes induced robust proliferation and prototypical superantigen-induced cytokine reaction when exposed to human CD4+/CD8+ cells. The β-globin lentiviral vector therefore produces a high level of functional, erythroid-specific immune modulators and cytotoxics that circulate without toxicity. Coupled with their unique ability to target and occlude hypoxic tumor vessels these armed SSRBCs constitute a potentially useful tool for treatment of solid tumors.

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Staphylococcal Superantigens of the Enterotoxin Gene Cluster (egc) for Treatment of Stage IIIb Non–Small Cell Lung Cancer with Pleural Effusion

Cited by 13 publications

References 83 publications

Staphylococcal entertotoxins of the enterotoxin Gene cluster (egcSEs) induce nitrous oxide- and cytokine dependent tumor cell apoptosis in a broad panel of human tumor cells

Staphylococcal entertotoxins of the enterotoxin Gene cluster (egcSEs) induce nitrous oxide- and cytokine dependent tumor cell apoptosis in a broad panel of human tumor cells

Mechanism of Monoclonal Antibody-Coupled Staphylococcus Superantigen-A Induced Apoptosis in Human Bladder Cancer Cells

Sickle cells produce functional immune modulators and cytotoxics

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