A Peptide Inhibitor of FOXP3 Impairs Regulatory T Cell Activity and Improves Vaccine Efficacy in Mice

Casares, Noëlia; Rudilla, Francesc; Arribillaga, Laura; Llópiz, Diana; Riezu-Boj, José Ignacio; Lozano, Teresa; López‐Sagaseta, Jacinto; Guembe, Laura; Sarobe, Pablo; Prieto, Jesús; Borrás‐Cuesta, Francisco; Lasarte, Juan José

doi:10.4049/jimmunol.1001114

Cited by 103 publications

(121 citation statements)

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“…For instance, in the CT26 tumor model the antibody mediated depletion of CD25 + T-cells (including Tregs) before immunization with tumor antigen AH1 resulted in long-lasting memory T-cell responses and even augmented a tumor-induced CD4 + T-cell response [56]. In another study, vaccination with AH1 tumor antigen in combination with the FOXP3-binding P60 peptide, which reduces the suppressive function of Tregs by preventing the nuclear translocation of FOXP3 and thus its ability to suppress the transcription factor NF-κB and NFAT, efficiently protected mice against CT26 tumor growth [106]. Likewise, antibody-mediated depletion of CD4 + CD25 + Tregs before vaccination with DCs loaded with tumor cells, that had been stressed by heat shock and irradiation, resulted in a delayed tumor outgrowth and long-lived tumor-protective immune responses [57].…”

Section: Other Interventions Applied Before Vaccination That Reduce Imentioning

confidence: 99%

The importance of correctly timing cancer immunotherapy

Nejad

Welters

Arens

et al. 2016

Expert Opinion on Biological Therapy

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Introduction:The treatment options for cancer-surgery, radiotherapy and chemotherapy-are now supplemented with immunotherapy. Previously underappreciated but now gaining strong interest are the immune modulatory properties of the three conventional modalities. Moreover, there is a better understanding of the needs and potential of the different immune therapeutic platforms. Key to improved treatment will be the combinations of modalities that complete each other's shortcomings. Area covered: Tumor-specific T-cells are required for optimal immunotherapy. In this review, the authors focus on the correct timing of different types of chemotherapeutic agents or immune modulators and immunotherapeutic drugs, not only for the activation and expansion of tumor-specific Tcells but also to support and enhance their anti-tumor efficacy. Expert opinion: At an early phase of disease, clinical success can be obtained using single treatment modalities but at later disease stages, combinations of several modalities are required. The gain in success is determined by a thorough understanding of the direct and indirect immune effects of the modalities used. Profound knowledge of these effects requires optimal tuning of immunomonitoring. This will guide the appropriate combination of treatments and allow for correct sequencing the order and interval of the different therapeutic modalities. ARTICLE HISTORY

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Section: Other Interventions Applied Before Vaccination That Reduce Imentioning

confidence: 99%

The importance of correctly timing cancer immunotherapy

Nejad

Welters

Arens

et al. 2016

Expert Opinion on Biological Therapy

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“…T cell proliferation was measured 3 d later as previously described (24). IFN-g secretion to the culture supernatant was measured by ELISA (BD Pharmingen).…”

Section: Retroviral Transduction Experimentsmentioning

confidence: 99%

“…Measurement of CD4 + T cell proliferation (CFSE dilution) was measured by flow cytometry. T cell proliferation and cytokine production were measured in splenocytes from BALB/c, C57BL/6, or DO11 mice as described (24).…”

Section: Retroviral Transduction Experimentsmentioning

confidence: 99%

Inhibition of FOXP3/NFAT Interaction Enhances T Cell Function after TCR Stimulation

Lozano

Villanueva

Durantez

et al. 2015

The Journal of Immunology

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Regulatory T cell (Treg) activity is modulated by a cooperative complex between the transcription factor NFAT and FOXP3, a lineage specification factor for Tregs. FOXP3/NFAT interaction is required to repress expression of IL-2, upregulate expression of the Treg markers CTLA4 and CD25, and confer suppressor function to Tregs. However, FOXP3 is expressed transiently in conventional CD4+ T cells upon TCR stimulation and may lead to T cell hyporesponsiveness. We found that a short synthetic peptide able to inhibit FOXP3/NFAT interaction impaired suppressor activity of conventional Tregs in vitro. Specific inhibition of FOXP3/NFAT interaction with this inhibitory peptide revealed that FOXP3 downregulates NFAT-driven promoter activity of CD40L and IL-17. Inhibition of FOXP3/NFAT interaction upregulated CD40L expression on effector T cells and enhanced T cell proliferation and IL-2, IFN-γ, IL-6, or IL-17 production in response to TCR stimulation. The inhibitory peptide impaired effector T cell conversion into induced Tregs in the presence of TGF-β. Moreover, in vivo peptide administration showed antitumor efficacy in mice bearing Hepa129 or TC1 tumor cells when combined with sorafenib or with an antitumor vaccine, respectively. Our results suggest that inhibition of NFAT/FOXP3 interaction might improve antitumor immunotherapies.

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“…In addition, the synthetic peptide, P60 (RDFQSFRKMWPFFAM) [219], has demonstrated potential of inhibiting the immunosuppressive activity of murine and human derived regulatory T-cells and enhances the effector T-cell stimulation in vitro by binding to regulatory T-cells specific forkhead or winged helix transcription factor 3. Thus, P60 can improve the immunogenicity of cancer and viral vaccines against CT26 tumor challenge and hepatitis C virus infection.…”

Section: Commercial Potential Of Milk Derived Proteins and Peptidesmentioning

confidence: 99%