Adjuvant immunotherapy of C6 glioma in rats with pertussis toxin

Orozco‐Morales, Mario; Sánchez-García, Francisco-Javier; Guevara-Salazar, Patricia; Arrieta, Óscar; Hernández‐Pedro, Norma; Sánchez-García, Aurora; Perez-Madrigal, Rodolfo; Rangel-López, Edgar; Pineda, Benjamín; Sotelo, Julio

doi:10.1007/s00432-011-1069-y

Cited by 13 publications

(10 citation statements)

References 49 publications

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“…The effects of PT on HGG cell migration, invasion, and vimentin expression, in the absence of substantial effects on HGG cell survival and proliferation, indicate specificity in the PT receptors and systems targeted. Furthermore, the selective effects of PT on cell migration suggest that off-target effects on non-tumor cells may by controllable, as indicated by previous studies [15–17]. We conclude that PT and/or newly developed drugs with overlapping targets merit further study as therapies for HGG.…”

Section: Discussionsupporting

confidence: 68%

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Pertussis Toxin Is a Robust and Selective Inhibitor of High Grade Glioma Cell Migration and Invasion

et al. 2016

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In high grade glioma (HGG), extensive tumor cell infiltration of normal brain typically precludes identifying effective margins for surgical resection or irradiation. Pertussis toxin (PT) is a multimeric complex that inactivates diverse Gi/o G-protein coupled receptors (GPCRs). Despite the broad continuum of regulatory events controlled by GPCRs, PT may be applicable as a therapeutic. We have shown that the urokinase receptor (uPAR) is a major driver of HGG cell migration. uPAR-initiated cell-signaling requires a Gi/o GPCR, N-formyl Peptide Receptor 2 (FPR2), as an essential co-receptor and is thus, PT-sensitive. Herein, we show that PT robustly inhibits migration of three separate HGG-like cell lines that express a mutated form of the EGF Receptor (EGFR), EGFRvIII, which is constitutively active. PT also almost completely blocked the ability of HGG cells to invade Matrigel. In the equivalent concentration range (0.01–1.0 μg/mL), PT had no effect on cell survival and only affected proliferation of one cell line. Neutralization of EGFRvIII expression in HGG cells, which is known to activate uPAR-initiated cell-signaling, promoted HGG cell migration. The increase in HGG cell migration, induced by EGFRvIII neutralization, was entirely blocked by silencing FPR2 gene expression or by treating the cells with PT. When U87MG HGG cells were cultured as suspended neurospheres in serum-free, growth factor-supplemented medium, uPAR expression was increased. HGG cells isolated from neurospheres migrated through Transwell membranes without loss of cell contacts; this process was inhibited by PT by >90%. PT also inhibited expression of vimentin by HGG cells; vimentin is associated with epithelial-mesenchymal transition and worsened prognosis. We conclude that PT may function as a selective inhibitor of HGG cell migration and invasion.

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Section: Discussionsupporting

confidence: 68%

“…In preclinical rodent model systems, systemically administered PT has demonstrated efficacy in counteracting hypertension [14]. PT was effective against tumors in a C6 glioma model and in an RG2 glioma model in combination with temozolomide [15, 16]. Signs of toxicity that might preclude further testing of PT were not reported.…”

Section: Introductionmentioning

confidence: 99%

Pertussis Toxin Is a Robust and Selective Inhibitor of High Grade Glioma Cell Migration and Invasion

et al. 2016

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“…18 Last, pertussis toxin was used in the same model as a potent immunotherapeutic factor. 19 Moreover, using the model we were able to exclude the possibility of alloimmune response because only solitary cells carrying particular CD types were detected on histochemical patterns related to brain sections of control animals (Fig. 6).…”

Section: Discussionmentioning

confidence: 99%

Effective immunotherapy of rat glioblastoma with prolonged intratumoral delivery of exogenous heat shock protein Hsp70

Shevtsov

Pozdnyakov

Mikhrina

et al. 2014

Intl Journal of Cancer

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Chaperone Hsp70 can activate adaptive immunity suggesting its possible application as an antitumor vaccine. To assess the therapeutic capacity of Hsp70 we administered purified chaperone into a C6 glioblastoma brain tumor and explored the viability and tumor size as well as interferon gamma (IFNc) production and cytotoxicity of lymphocytes in the treated animals. Targeted intratumoral injection of Hsp70 resulted in its distribution within the area of glioblastoma, and caused significant inhibition of tumor progression as confirmed by magnetic resonance imaging. The delay in tumor growth corresponded to the prolonged survival of tumor-bearing animals of up to 31 days versus 20 days in control. Continuous administration of Hsp70 with an osmotic pump increased survival even further (39 days). Therapeutic efficacy was associated with infiltration to glioblastoma of NK cells (Ly-6c1) and T lymphocytes (CD31, CD41 and CD81) as well as with an increase in the activity of NK cells (granzyme B production) and CD81 T lymphocytes as shown by IFNc ELISPOT assay. Furthermore, we found that Hsp70 treatment caused concomitantly, with a tenfold elevated IFNc production, an increase in anti-C6 tumor cytotoxicity of lymphocytes. In conclusion, continuous intratumoral delivery of Hsp70 demonstrates high therapeutic potential and therefore could be applied in the treatment of glioblastoma.Multiform glioblastoma is the most aggressive and common primary brain tumor in adults 1 with an incidence rate of 7.3 cases per 100,000 persons per year.2 The standard treatment for newly diagnosed glioblastoma currently includes surgical resection followed by radiotherapy and chemotherapy using apoptosis-inducing factors such as temozolomide, which is actively used nowadays. 3During the last two decades, increasing evidence has demonstrated that the high immunomodulatory potency of heat shock protein 70 (Hsp70) is due to its ability to specifically bind tumor antigens and present them to dendritic antigenpresenting cells (APCs).4 Several anticancer and antivirus vaccines were created based on Hsp70 chaperone. First, immunization of mice bearing tumors with Hsp70-secreting murine ovarian cancer cells caused a strong anticancer effect concomitantly with the elicitation of CD41 and CD81 Tand NK-cell activity.5 Another chaperonic vaccine contains fusion products of Hsp70 with Herpes virus VP22 peptide (aa268-301) that facilitate intracellular transport; this construct was effective in inducing a specific cytotoxic response against mouse lymphoma cells.6 Third, Ito et al. showed that the combined intratumoral delivery of pure Hsp70 with heating magnetic particles can efficiently destroy mouse melanoma B16 in a therapeutic modality. 7 More recently, we reported that the application of purified Hsp70 onto skin area covering B16/F10 melanoma significantly inhibited tumor progression and increased the survival of animals. 8Although the mechanism of antitumor activity of Hsp70 remains unclear, it is believed that the chaperone can trigger both innate and ...

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“…The precise mechanism and the specific molecular targets of this activity remain to be investigated. Recently, the ability of PTX to decrease the number of regulatory T cells was exploited in an experimental model of immunotherapy against C6 glioma in rats [88].…”

Section: Ptx Modulates Innate and Adaptive Immune Responsesmentioning

confidence: 99%

Investigating Pertussis Toxin and its Impact on Vaccination

Coutte

Locht

2015

Future Microbiol.

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Whooping cough, caused by Bordetella pertussis, remains a major global health problem. Each year around 40 million of pertussis cases resulting in 200,000-400,000 annual deaths occur worldwide. Pertussis toxin is a major virulence factor of B. pertussis. Murine studies have shown its importance in bacterial colonization and in immunomodulation to evade innate or adaptive immunity. The toxin is composed of an A protomer expressing ADP-ribosyltransferase activity and a B oligomer, responsible for toxin binding to target cells. The toxin is also a major protective antigen in all currently available vaccines. However, vaccine escape mutants with altered toxin expression have recently been isolated in countries with high vaccination coverage illustrating the need for improved pertussis vaccines.

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Adjuvant immunotherapy of C6 glioma in rats with pertussis toxin

Abstract: These results suggest that PTx could be an immunotherapeutic adjuvant in the integral therapy against glial tumors.

Cited by 13 publications

References 49 publications

Pertussis Toxin Is a Robust and Selective Inhibitor of High Grade Glioma Cell Migration and Invasion

Pertussis Toxin Is a Robust and Selective Inhibitor of High Grade Glioma Cell Migration and Invasion

Effective immunotherapy of rat glioblastoma with prolonged intratumoral delivery of exogenous heat shock protein Hsp70

Investigating Pertussis Toxin and its Impact on Vaccination

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