Apoptosis of CD4+CD25high T cells in response to Sirolimus requires activation of T cell receptor and is modulated by IL-2

Molhoek, Kerrington R.; McSkimming, Chantel; Olson, Walter C.; Brautigan, David L.; Slingluff, Craig L.

doi:10.1007/s00262-008-0602-6

Cited by 31 publications

(25 citation statements)

References 29 publications

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“…However, most results supporting this statement have been obtained with anti-VEGF mAb or the tyrosine kinase inhibitor, sunitinib. Preliminary results showed that this activity of some antiangiogenic on the immune system could not be extended to all antiangiogenic molecules [61,142]. It suggests that the current dogma regarding VEGF as the main target of antiangiogenic for the reversal of immunosuppression has to be questioned.…”

Section: Discussionmentioning

confidence: 87%

Angiogenesis and immunity: a bidirectional link potentially relevant for the monitoring of antiangiogenic therapy and the development of novel therapeutic combination with immunotherapy

Tartour

Péré

Maillère

et al. 2011

Cancer Metastasis Rev

279

205

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The immune system regulates angiogenesis in cancer with both pro- and antiangiogenic activities. The induction of angiogenesis is mediated by tumor-associated macrophages and myeloid-derived suppressor cells (MDSC) which produce proinflammatory cytokines, endothelial growth factors (VEGF, bFGF…), and protease (MMP9) implicated in neoangiogenesis. Some cytokines (IL-6, IL-17…) activated Stat3 which also led to the production of VEGF and bFGF. In contrast, other cytokines (IFN, IL-12, IL-21, and IL-27) display an antiangiogenic activity. Recently, it has been shown that some antiangiogenic molecules alleviates immunosuppression associated with cancer by decreasing immunosuppressive cells (MDSC, regulatory T cells), immunosuppressive cytokines (IL-10, TGFβ), and inhibitory molecules on T cells (PD-1). Some of these broad effects may result from the ability of some antiangiogenic molecules, especially cytokines to inhibit the Stat3 transcription factor. The association often observed between angiogenesis and immunosuppression may be related to hypoxia which induces both neoangiogenesis via activation of HIF-1 and VEGF and favors the intratumor recruitment and differentiation of regulatory T cells and MDSC. Preliminary studies suggest that modulation of immune markers (intratumoral MDSC and IL-8, peripheral regulatory T cells…) may predict clinical response to antiangiogenic therapy. In preclinical models, a synergy has been observed between antiangiogenic molecules and immunotherapy which may be explained by an improvement of immune status in tumor-bearing mice after antiangiogenic therapy. In preclinical models, antiangiogenic molecules promoted intratumor trafficking of effector cells, enhance endogenous anti-tumor response, and synergyzed with immunotherapy protocols to cure established murine tumors. All these results warrant the development of clinical trials combining antiangiogenic drugs and immunotherapy.

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Section: Discussionmentioning

confidence: 87%

Angiogenesis and immunity: a bidirectional link potentially relevant for the monitoring of antiangiogenic therapy and the development of novel therapeutic combination with immunotherapy

Tartour

Péré

Maillère

et al. 2011

Cancer Metastasis Rev

279

205

View full text Add to dashboard Cite

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“…29,36 With respect to the effect of other antiangiogenic molecules on regulatory T cells, variable results were reported. 36,43,44 The targeting of molecules other than VEGF by some antiangiogenic drugs may explain this heterogeneity.…”

Section: Discussionmentioning

confidence: 99%

A Decrease of Regulatory T Cells Correlates With Overall Survival After Sunitinib-based Antiangiogenic Therapy in Metastatic Renal Cancer Patients

Adotévi

Péré²,

Ravel³

et al. 2010

Journal of Immunotherapy

187

129

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Sunitinib, an antiangiogenic molecule, is one of the first-line standard of care in the treatment of patients with metastatic renal cell carcinoma. However, it only benefits to a subgroup of patients and no predictive markers of sunitinib efficacy have been identified. Twenty-eight metastatic renal cell carcinomas were treated with sunitinib-based therapy and another subgroup of 7 primary renal cell cancer patients were also treated by sunitinib in a neoadjuvant trial. Measurements of CD3+CD4+CD25(hi) Foxp3+ regulatory T cells, an immunosuppressive cell population, were performed before and after each cycle of treatment in blood and tumor in a prospective study. We observed a decrease in the number of peripheral blood Foxp3+ regulatory T cells after each cycle of sunitinib-based therapy. The overall survival was significantly longer in patients showing a decrease in the number of Foxp3+ regulatory T cells after 2 or 3 cycles of treatment (P<0.05). The decrease in the number of regulatory T cells positively correlated with their number at baseline (P<0.01), but not with modification of tumor volume defined by Response Evaluation Criteria in Solid Tumors criteria. The clinical relevance of these results was also supported by an intratumoral decrease of regulatory T cells in 5 out of 7 patients treated by sunitinib in a neoadjuvant trial. Our study represents the first work reporting that the measurement of regulatory T cells may have a predictive value on antiangiogenic response. Antiangiogenic therapy also reversed immunosuppression in the tumor microenvironment which provides novel argument in human to favor its combination with immunotherapy.

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“…As a result, mitochondrial membranes can depolarize, production of caspase 3 can be up-regulated, and the intrinsic pathway of cellular apoptosis can be stimulated [206]. The net consequence of mTOR inhibition is an impairment of the cellular immune response [207] (Fig. 1).…”

Section: Rapamycinmentioning

confidence: 98%

“…Importantly, regulatory (CD4 + CD25 + ) T cells are resistant to the apoptosis induced by rapamycin, and they are advantaged by the drug [209]. Their preferential survival is mediated by IL-2, and rapamycin is maximally effective during periods of active antigenic stimulation and IL-2 production [207]. The selective survival of the regulatory T cell population further suppresses the adaptive immune response.…”

Section: Rapamycinmentioning

confidence: 98%

Nonstandard Drugs and Feasible New Interventions for Autoimmune Hepatitis: Part I

Czaja¹

2012

IADT

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Nonstandard drugs that target critical pathogenic pathways or immune regulatory mechanisms constitute the next generation of treatments for autoimmune hepatitis. Mycophenolate mofetil impairs the proliferation of lymphocytes, decreases autoantibody production, and induces apoptosis of activated immunocytes. Patients treated for azathioprine intolerance improve more frequently than patients treated for refractory liver disease (54% versus 10%), and mycophenolate mofetil is emerging as a rescue therapy for this population. Complete corticosteroid withdrawal is possible in 40% of patients treated with mycophenolate mofetil, and the frequency of side effects ranges from 3-34%. Budesonide in combination with azathioprine has normalized liver tests more frequently (47% versus 18%) and with fewer side effects (28% versus 53%) than standard therapy after 6 months. Budesonide is emerging as a frontline treatment in non-cirrhotic patients with uncomplicated disease or contraindications to conventional corticosteroids. Cyclosporine and tacrolimus are effective salvage agents for steroid-refractory disease, but side effects have been common and occasionally serious. The 6- thioguanine nucleotides and rapamycin are feasible treatments for autoimmune hepatitis, but 6-thioguanine has major obstacles to overcome, especially the risk of liver toxicity or nodular regenerative hyperplasia. The nonstandard drug therapies emerging for autoimmune hepatitis reflect the need to supplement or supplant current treatment regimens. None has been licensed for use in autoimmune hepatitis, and their applications have been based on results from small singlecenter experiences.

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Apoptosis of CD4+CD25high T cells in response to Sirolimus requires activation of T cell receptor and is modulated by IL-2

Cited by 31 publications

References 29 publications

Angiogenesis and immunity: a bidirectional link potentially relevant for the monitoring of antiangiogenic therapy and the development of novel therapeutic combination with immunotherapy

Angiogenesis and immunity: a bidirectional link potentially relevant for the monitoring of antiangiogenic therapy and the development of novel therapeutic combination with immunotherapy

A Decrease of Regulatory T Cells Correlates With Overall Survival After Sunitinib-based Antiangiogenic Therapy in Metastatic Renal Cancer Patients

Nonstandard Drugs and Feasible New Interventions for Autoimmune Hepatitis: Part I

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