Nuestros investigadores

Teresa Lozano Moreda

Publicaciones científicas más recientes (desde 2010)

Autores: Ajona, Daniel; et al.
Revista: NATURE CANCER
ISSN 2662-1347  Vol. 1  2020  págs. 75 - 85
Harnessing the immune system by blocking the programmed cell death protein 1 (PD-1) pathway has been a major breakthrough in non-small-cell lung cancer treatment. Nonetheless, many patients fail to respond to PD-1 inhibition. Using three syngeneic models, we demonstrate that short-term starvation synergizes with PD-1 blockade to inhibit lung cancer progression and metastasis. This antitumor activity was linked to a reduction in circulating insulin-like growth factor 1 (IGF-1) and a downregulation of IGF-1 receptor (IGF-1R) signaling in tumor cells. A combined inhibition of IGF-1R and PD-1 synergistically reduced tumor growth in mice. This effect required CD8 cells, boosted the intratumoral CD8/Treg ratio and led to the development of tumor-specific immunity. In patients with non-small-cell lung cancer, high plasma levels of IGF-1 or high IGF-1R expression in tumors was associated with resistance to anti-PD-1¿programmed death-ligand 1 immunotherapy. In conclusion, our data strongly support the clinical evaluation of IGF-1 modulators in combination with PD-1 blockade.
Autores: Setiawan, M. F. ; Rudan, O.; Vogt, A.; et al.
Revista: ANTICANCER RESEARCH
ISSN 0250-7005  Vol. 39  Nº 10  2019  págs. 5369 - 5374
Background/Aim: Cytokine-induced killer (CIK) cells are ex vivo expanded major histocompatibility complex (MHC)-unrestricted cytotoxic cells with promising effects against a variety of cancer types. Regulatory T-cells (T-reg) have been shown to reduce the effectiveness of CIK cells against tumor cells. Peptide P60 has been shown to inhibit the immunosuppressive functions of T-regs. This study aimed at examining the effect of p60 on CIK cells efficacy against renal and pancreatic cancer cells. Materials and Methods: The effect of P60 on CIK cytotoxicity was examined using flow cytometry, WST-8-based cell viability assay and interferon gamma (IFN gamma) ELISA. Results: P60 treatment resulted in a significant decrease in the viability of renal and pancreatic cancer cell lines co-cultured with CIK cells. No increase in IFN gamma secretion from CIK cells was detected following treatment with P60. P60 caused no changes in the distribution of major effector cell populations in CIK cell cultures. Conclusion: P60 may potentiate CIK cell cytotoxicity against tumor cells.
Autores: Aritz Lasarte-Cia; et al.
Revista: FRONTIERS IN IMMUNOLOGY
ISSN 1664-3224  Vol. 9  Nº JAN  2018  págs. Article number: 68
A complex network of interactions exists between the immune, the olfactory, and the central nervous system (CNS). Inhalation of different fragrances can affect immunological reactions in response to an antigen but also may have effects on the CNS and cognitive activity. We performed an exploratory study of the immunomodulatory ability of a series of compounds representing each of the 10 odor categories or clusters described previously. We evaluated the impact of each particular odor on the immune response after immunization with the model antigen ovalbumin in combination with the TLR3 agonist poly I:C. We found that some odors behave as immunostimulatory agents, whereas others might be considered as potential immunosuppressant odors. Interestingly, the immunomodulatory capacity was, in some cases, strain-specific. In particular, one of the fragrances, carvone, was found to be immunostimulatory in BALB/c mice and immunosuppressive in C57BL/6J mice, facilitating or impairing viral clearance, respectively, in a model of a viral infection with a recombinant adenovirus. Importantly, inhalation of the odor improved the memory capacity in BALB/c mice in a fear-conditioning test, while it impaired this same capacity in C57BL/6J mice. The improvement in memory capacity in BALB/c was associated with higher CD3+ T cell infiltration into the hippocampus and increased local expression of mRNA coding for IL-1ß, TNF-¿, and IL-6 cytokines. In contrast, the memory impairment in C57BL/6 was associated with a reduction in CD3 numbers and an increase in IFN-¿. These data suggest an association between the immunomodulatory capacity of smells and their impact on the cognitive functions of the animals. These results highlight the potential of studying odors as therapeutic agents for CNS-related diseases.
Autores: Llopiz, Diana Isabel; Ruiz, Marta; et al.
Revista: ONCOIMMUNOLOGY
ISSN 2162-4011  Vol. 7  Nº 4  2018  págs. Article: e1409321
Tumor infiltrating lymphocytes have been associated with a better prognostic and with higher response rates in patients treated with checkpoint inhibiting antibodies, suggesting that strategies promoting tumor inflammation may enhance the efficacy of these currently available therapies. Our aim was thus to develop a new vaccination platform based on cold-inducible RNA binding protein (CIRP), an endogenous TLR4 ligand generated during inflammatory processes, and characterize whether it was amenable to combination with checkpoint inhibitors. In vitro, CIRP induced dendritic cell activation, migration and enhanced presentation of CIRP-bound antigens to T-cells. Accordingly, antigen conjugation to CIRP conferred immunogenicity, dependent on immunostimulatory and antigen-targeting capacities of CIRP. When applied in a therapeutic setting, vaccination led to CD8-dependent tumor rejection in several tumor models. Moreover, immunogenicity of this vaccination platform was enhanced not only by combination with additional adjuvants, but also with antibodies blocking PD-1/PD-L1, CTLA-4 and IL-10, immunosuppressive molecules usually present in the tumor environment and also induced by the vaccine. Therefore, priming with a CIRP-based vaccine combined with immune checkpoint-inhibiting antibodies rejected established B16-OVA tumors. Finally, equivalent activation and T-cell stimulatory effects were observed when using CIRP in vitro with human cells, suggesting that CIRP-based vaccination strategies could be a valuable clinical tool to include in combinatorial immunotherapeutic strategies in cancer patients.
Autores: Gorraiz, Marta; Lasarte-Cía, A.; et al.
Revista: ONCOTARGET
ISSN 1949-2553  Vol. 8  Nº 42  2017  págs. 71709 - 71724
Although T regulatory cells (Treg) are essential for the prevention of autoimmune diseases, their immunoregulatory function restrains the induction of immune responses against cancer. Thus, development of inhibitors of FOXP3, a key transcription factor for the immunosuppressive activity of Treg, might give new therapeutic opportunities. In a previous work we identified a peptide (named P60) able to enter into the cells, bind to FOXP3, and impair Treg activity in vitro and in vivo. Here we show that P60 binds to the intermediate region of FOXP3 and inhibits its homodimerization as well as its interaction with the transcription factor AML1. Alanine-scanning of P60 revealed the relevance of each position on FOXP3 binding, homodimerization, association with AML1 and inhibition of Treg activity. Introduction of alanine at positions 2, 5 and 11 improved the activity of the original P60, whereas alanine mutations at positions 1, 7, 8, 9, 10 and 12 were detrimental. Multiple mutation experiments allowed us to identify peptides with higher FOXP3 binding affinity and stronger biological activity than the original P60. Head to tail macrocyclization of peptide P60-D2A-S5A improved Treg inhibition and enhanced anti-tumor activity of anti-PD1 antibodies in a model of hepatocellular carcinoma. Introduction of a D-aminoacid at position 2 augmented significantly microsomal stability while maintained FOXP3 binding capacity and Treg inhibition in vitro. In vivo, when combined with the cytotoxic T-cell epitope AH1, it induced protection against CT26 tumor implantation. This study provides important structure¿function relationships essential for further drug design to inhibit Treg cells in cancer.
Autores: Celay, J.; Concepcion, A. R.; et al.
Revista: HAEMATOLOGICA-THE HEMATOLOGY JOURNAL
ISSN 0390-6078  Vol. 103  Nº 6  2017  págs. 1065 - 1072
Regulatory T (Treg) cells can weaken antitumor immune responses, and inhibition of their function appears as a promising immunotherapeuticimmunotherapy therapeutic approach in cancer patients. Mice with targeted deletion of the gene encoding the Cl-HCO3-anion exchanger AE2 (also termed SLC4A2), a membrane-bound carrier involved in intracellular pH regulation, showed a progressive decrease in the number of Treg cells. We therefore challenged AE2 as a potential target for tumor immune therapy, and generated linear peptides designed to bind the third extracellular loop of AE2, which is crucial for its exchange activity. Peptide p17AE2 exhibited optimal interaction ability and indeed promoted apoptosis in mouse and human Treg cells, while activating effector T-cell function. Interestingly, this linear peptide also induced apoptosis in different types of human B-cell leukemia, lymphoma and multiple myeloma cell lines and primary malignant samples, while it showed only moderate effects on normal B lymphocytes. Finally, a macrocyclic peptide exhibiting increased stability in vivo was effective in mice xenografted with B-cell lymphoma. These data suggest that targeting the anion exchanger AE2 with specific peptides may represent an effective therapeutic approach in B-cell malignancies
Autores: Sandra Hervas-Stubbs; et al.
Revista: PLOS ONE
ISSN 1932-6203  Vol. 12  Nº 9  2017  págs. e0185169
LAG3 receptor belongs to a family of immune-checkpoints expressed in T lymphocytes and other cells of the immune system. It plays an important role as a rheostat of the immune response. Focus on this receptor as a potential therapeutic target in cancer immunotherapy has been underscored after the success of other immune-checkpoint blockade strategies in clinical trials. LAG3 showcases the interest in the field of autoimmunity as several studies show that LAG3-targeting antibodies can also be used for the treatment of autoimmune diseases. In this work we describe the identification of a high-affinity LAG3 aptamer by High Throughput Sequencing SELEX in combination with a study of potential conserved binding modes according to sequence conservation by using 2D-structure prediction and 3D-RNA modeling using Rosetta. The aptamer with the highest accumulation of these conserved sequence motifs displays the highest affinity to LAG3 recombinant soluble proteins and binds to LAG3-expressing lymphocytes. The aptamer described herein has the potential to be used as a therapeutic agent, as it enhances the threshold of T-cell activation. Nonetheless, in future applications, it could also be engineered for treatment of autoimmune diseases by target depletion of LAG3-effector T lymphocytes.
Autores: Consuegra-Fernández, M.; Martínez-Florensa, M.; Aranda, F.; et al.
Revista: FRONTIERS IN IMMUNOLOGY
ISSN 1664-3224  Vol. 8  Nº 594  2017 
The CD6 lymphocyte receptor has been involved in the pathophysiology of different autoimmune disorders and is now considered a feasible target for their treatment. In vitro data show the relevance of CD6 in the stabilization of adhesive contacts between T-cell and antigen-presenting cells, and the modulation of T-cell receptor signals. However, the in vivo consequences of such a function are yet undisclosed due to the lack of suitable genetically modified animal models. Here, the in vitro and in vivo challenge of CD6-deficient (CD6(-/-)) cells with allogeneic cells was used as an approach to explore the role of CD6 in immune responses under relative physiological stimulatory conditions. Mixed lymphocyte reaction (MLR) assays showed lower proliferative responses of splenocytes from CD6(-/-)mice together with higher induction of regulatory T cells (T-reg, CD4(+)CD25(+)FoxP3(+)) with low suppressive activity on T and B-cell proliferation. In line with these results, CD6(-/-)mice undergoing a lupus-like disorder induced by chronic graft-versus-host disease (cGvHD) showed higher serum titers of anti-double-stranded DNA and nucleosome autoantibodies. This occurred together with reduced splenomegaly, which was associated with lower in vivo bromodesoxyuridine incorporation of spleen cells and with increased percentages of spleen follicular B cells (B2, CD21(+)CD23(hi)) and T-reg cells. Interestingly, functional analysis of in vivo-generated CD6(-/-)T(reg) cells exhibited defective suppressive activity. In conclusion, the data from MLR and cGvHD-induced lupus-like models in CD6(-/-)mice illustrate the relevance of CD6 in T (and B) cell proliferative responses and, even more importantly, Treg induction and suppressive function in the in vivo maintenance of peripheral tolerance.
Autores: Ajona, Daniel; Ortiz Espinosa, S.; Moreno, H. ; et al.
Revista: CANCER DISCOVERY
ISSN 2159-8274  Vol. 7  Nº 7  2017  págs. 694 - 703
Disruption of the programmed cell death protein 1 (PD-1) pathway with immune checkpoint inhibitors represents a major breakthrough in the treatment of non-small cell lung cancer. We hypothesized that combined inhibition of C5a/C5aR1 and PD-1 signaling may have a synergistic antitumor effect. The RMP1-14 antibody was used to block PD-1, and an L-aptamer was used to inhibit signaling of complement C5a with its receptors. Using syngeneic models of lung cancer, we demonstrate that the combination of C5a and PD-1 blockade markedly reduces tumor growth and metastasis and leads to prolonged survival. This effect is accompanied by a negative association between the frequency of CD8 T cells and myeloid-derived suppressor cells within tumors, which may result in a more complete reversal of CD8 T-cell exhaustion. Our study provides support for the clinical evaluation of anti-PD-1 and anti-C5a drugs as a novel combination therapeutic strategy for lung cancer. SIGNIFICANCE: Using a variety of preclinical models of lung cancer, we demonstrate that the blockade of C5a results in a substantial improvement in the efficacy of anti-PD-1 antibodies against lung cancer growth and metastasis. This study provides the preclinical rationale for the combined blockade of PD-1/PD-L1 and C5a to restore antitumor immune responses, inhibit tumor cell growth, and improve outcomes of patients with lung cancer. (C) 2017 AACR.
Autores: Fernandez-Poma, S. M.; Salas, Diego; et al.
Revista: CANCER RESEARCH
ISSN 0008-5472  Vol. 77  Nº 13  2017  págs. 3672 - 3684
Recent studies have found that tumor-infiltrating lymphocytes (TIL) expressing PD-1 can recognize autologous tumor cells, suggesting that cells derived from PD-1(+) TILs can be used in adoptive T-cell therapy (ACT). However, no study thus far has evaluated the antitumor activity of PD-1-selected TILs in vivo. In two mouse models of solid tumors, we show that PD-1 allows identification and isolationof tumor-specific TILs without previous knowledge of their antigen specificities. Importantly, despite the high proportion of tumor-reactive T cells present in bulk CD8 TILs before expansion, only T-cell products derived fromsorted PD-1(+), but not from PD-1(-) or bulk CD8 TILs, specifically recognized tumor cells. The fold expansion of PD-1(+) CD8 TILs was 10 times lower than that of PD-1(-) cells, suggesting that outgrowth of PD-1(-) cells was the limiting factor in the tumor specificity of cells derived from bulk CD8 TILs. The highly differentiated state of PD-1(+) cells was likely the main cause hampering ex vivo expansion of this subset. Moreover, PD-1 precisely identified marrow-infiltrating, myeloma-specific T cells in a mouse model of multiple myeloma. In vivo, only cells expanded from PD-1(+) CD8 TILs contained tumor progression, and their efficacy was enhanced by PDL-1 blockade. Overall, our data provide a rationale for the use of PD-1-selected TILs in ACT. (C) 2017 AACR.
Autores: Gorraiz, Marta; et al.
Revista: JOURNAL OF IMMUNOLOGY
ISSN 0022-1767  Vol. 195  Nº 7  2015  págs. 3180 - 3189
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-¿, 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-ß. 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.
Autores: Matsoukas, M.-T.; Aranguren-Ibáñez, A.; et al.
Revista: SCIENCE SIGNALING
ISSN 1945-0877  Vol. 8  Nº 382  2015  págs. ra63
Calcineurin (CN), a serine and threonine protein phosphatase that depends on Ca2+ and calmodulin for its activity, is the target of the immunosuppressant drugs cyclosporin A (CsA) and tacrolimus (FK506). CN dephosphorylates and activates members of the NFATc (nuclear factor of activated T cells) family of transcription factors in T cells by binding to their conserved PxIxIT motif. Upon dephosphorylation, NFATc proteins translocate to the nucleus, where they stimulate the expression of genes encoding cytokines and chemokines that are required for T cell proliferation and the immune response. We performed a pharmacophore-based virtual screening of ~5.5 million commercially available, "drug-like" compounds to identify nonpeptidic compounds that inhibited the CN-dependent activation of NFATc signaling and that could serve as potential drug candidates for immunosuppressive therapy. Of 32 compounds that mimicked the PxIxIT motif, 7 competed with NFATc for binding to CN in vitro without interfering with the phosphatase activity of CN. Furthermore, in activated human CD4+ T cells, four of the seven compounds inhibited the expression of NFATc-dependent genes, cytokine production, and cell proliferation, suggesting that these may have therapeutic potential as immunosuppressive agents.
Autores: Gato-Cañas, M. ; Martínez de Morentin, X. ; Blanco-Luquin, I. ; et al.
Revista: ONCOTARGET
ISSN 1949-2553  Vol. 6  Nº 29  2015  págs. 27160 - 27175
Myeloid-derived suppressor cells (MDSCs) differentiate from bone marrow precursors, expand in cancer-bearing hosts and accelerate tumor progression. MDSCs have become attractive therapeutic targets, as their elimination strongly enhances anti-neoplastic treatments. Here, immature myeloid dendritic cells (DCs), MDSCs modeling tumor-infiltrating subsets or modeling non-cancerous (NC)-MDSCs were compared by in-depth quantitative proteomics. We found that neoplastic MDSCs differentially expressed a core of kinases which controlled lineage-specific (PI3K-AKT and SRC kinases) and cancer-induced (ERK and PKC kinases) protein interaction networks (interactomes). These kinases contributed to some extent to myeloid differentiation. However, only AKT and ERK specifically drove MDSC differentiation from myeloid precursors. Interfering with AKT and ERK with selective small molecule inhibitors or shRNAs selectively hampered MDSC differentiation and viability. Thus, we provide compelling evidence that MDSCs constitute a distinct myeloid lineage distinguished by a "kinase signature" and well-defined interactomes. Our results define new opportunities for the development of anti-cancer treatments targeting these tumor-promoting immune cells.
Autores: Casares, N; Lasarte, Juan José;
Revista: FRONTIERS IN ONCOLOGY
ISSN 2234-943X  Vol. 3  2013  págs. 294
OXP3 is a multifaceted transcription factor with a major role in the control of immune homeostasis mediated by T regulatory cells (Treg). The immunoregulatory function of FOXP3 may hinder the induction of immune responses against cancer and infectious agents, and thus, development of inhibitors of its functions might give new therapeutic opportunities for these diseases. But also, FOXP3 is an important tumor suppressor factor in some types of cancers, and therefore, understanding the structure and function of FOXP3 is crucial to gaining insights into the development of FOXP3-targeted therapeutic strategies. FOXP3 homodimerize and likely form supramolecular complexes which might include hundreds of proteins which constitute the FOXP3 interactome. Many of the functions of FOXP3 are clearly regulated by the interactions with these cofactors contributing importantly on the establishment of Treg-cell signature. We summarize here the structural/functional information on this FOXP3 complex, to identify potential opportunities for the development of new strategies to modulate FOXP3 activity.
Autores:  et al.
Revista: BIOMED RESEARCH INTERNATIONAL
ISSN 2314-6133  2013  págs. 864720
The development of tools for efficient targeting of antigens to antigen presenting cells is of great importance for vaccine development. We have previously shown that fusion proteins containing antigens fused to the extra domain A from fibronectin (EDA), an endogenous TLR4 ligand, which targets antigens to TLR4-expressing dendritic cells (DC), are highly immunogenic. To facilitate the procedure of joining EDA to any antigen of choice, we have prepared the fusion protein EDAvidin by linking EDA to the N terminus of streptavidin, allowing its conjugation with biotinylated antigens. We found that EDAvidin, as streptavidin, forms tetramers and binds biotin or biotinylated proteins with a Kd ~ 2.6 × 10(-14) mol/L. EDAvidin favours the uptake of biotinylated green fluorescent protein by DC. Moreover, EDAvidin retains the proinflammatory properties of EDA, inducing NF- ¿ß by TLR4-expressing cells, as well as the production of TNF- ¿ by the human monocyte cell line THP1 and IL-12 by DC. More importantly, immunization of mice with EDAvidin conjugated with the biotinylated nonstructural NS3 protein from hepatitis C virus induces a strong anti-NS3 T cell immune response. These results open a new way to use the EDA-based delivery tool to target any antigen of choice to DC for vaccination against infectious diseases and cancer.
Autores: Casares, N; Lasarte, Juan José;
Revista: FRONTIERS IN ONCOLOGY
ISSN 2234-943X  Vol. 3  2013  págs. 294
FOXP3 is a multifaceted transcription factor with a major role in the control of immune homeostasis mediated by T regulatory cells (Treg). The immunoregulatory function of FOXP3 may hinder the induction of immune responses against cancer and infectious agents, and thus, development of inhibitors of its functions might give new therapeutic opportunities for these diseases. But also, FOXP3 is an important tumor suppressor factor in some types of cancers, and therefore, understanding the structure and function of FOXP3 is crucial to gaining insights into the development of FOXP3-targeted therapeutic strategies. FOXP3 homodimerize and likely form supramolecular complexes which might include hundreds of proteins which constitute the FOXP3 interactome. Many of the functions of FOXP3 are clearly regulated by the interactions with these cofactors contributing importantly on the establishment of Treg-cell signature. We summarize here the structural/functional information on this FOXP3 complex, to identify potential opportunities for the development of new strategies to modulate FOXP3 activity
Autores: Rudilla, F; Fayolle, C; Casares, N; et al.
Revista: VACCINE
ISSN 0264-410X  Vol. 30  Nº 18  2012  págs. 2848 - 2858
The complement system and Toll-like receptors (TLR) are key innate defense systems which might interact synergistically on dendritic cells (DC) to reinforce adaptive immunity. In a previous work, we found that the extra domain A from fibronectin EDA (an endogenous ligand for TLR4) can favour antigen delivery to DC and induce their maturation. Given the potential of anaphylatoxins to cause inflammation and activation of myeloid cells, we hypothesized that a fusion protein between EDA, and anaphylatoxins C3a, C4a or C5a together with an antigen might improve the immunogenicity of the antigen. Naked DNA immunization with a construct expressing the fusion protein between C5a, EDA and the cytotoxic T cell epitope SIINFEKL from ovalbumin, induced strong antigen specific T cell responses. The purified recombinant fusion protein EDA¿SIINFEKL¿C5a induced activation of dendritic cells, the production of proinflammatory cytokines/chemokines and stimulated antigen presenting cell migration and NK cell activation. As compared to EDA¿SIINFEKL, the fusion protein EDA¿SIINFEKL¿C5a did not induce the production of the immunosuppressive molecules IL-10, CCL17, CCL1, CXCL12 or XCL1 by DC. Moreover, EDA¿SIINFEKL¿C5a induced strong specific T cell responses in vivo and protected mice against E.G7-OVA tumor growth more efficiently than EDA¿SIINFEKL or SIINFEKL¿C5a recombinant proteins. Our results suggest that fusion proteins containing EDA, the anaphylatoxin C5a and the antigen may serve as a suitable strategy for the development of anti-tumor or anti-viral vaccines.
Autores: Berraondo, Pedro; et al.
Revista: INTERNATIONAL JOURNAL OF CANCER
ISSN 0020-7136  Vol. 131  Nº 3  2012  págs. 641 - 651
Cervical carcinoma is one of the most common cancers in women worldwide. It is well established that chronic infection of the genital tract by various mucosatropic human papillomavirus (HPV) types causes cervical cancer. Cellular immunity to E7 protein from HPV (HPVE7) has been associated with clinical and cytologic resolution of HPV-induced lesions. Thus, we decided to test if targeting of HPVE7 to dendritic cells using a fusion protein containing the extra domain A (EDA) from fibronectin, a natural ligand for TLR4, and HPVE7 (EDA-HPVE7) might be an efficient vaccine for the treatment of cervical carcinoma. We found that EDA-HPVE7 fusion protein was efficiently captured by bone marrow derived dendritic cells in vitro and induced their maturation, with the upregulation of maturation markers and the production of IL-12. Immunization of mice with EDA-HPVE7 fusion protein induced antitumor CD8+ T cell responses in the absence of additional adjuvants. Repeated intratumoral administration of EDA-HPVE7 in saline was able to cure established TC-1 tumors of 57 mm in diameter. More importantly, intravenous injection with EDA-HPVE7 in combination with the TLR ligand polyinosinic-polycytidylic acid (pIC), or with low doses of cyclophosphamide and the TLR9 ligand CpG-B complexed in cationic lipids, were able to eradicate large established TC-1 tumors (1.2 cm in diameter). Thus, therapeutic vaccination with EDA-HPVE7 fusion protein may be effective in the treatment of human cervical carcinoma.
Autores: Casares, N; et al.
Revista: JOURNAL OF IMMUNOLOGY
ISSN 0022-1767  Vol. 185  Nº 9  2010  págs. 5150 - 5159
Immunosuppressive activity of regulatory T cells (Treg) may contribute to the progression of cancer or infectious diseases by preventing the induction of specific immune responses. Using a phage-displayed random peptide library, we identified a 15-mer synthetic peptide, P60, able to bind to forkhead/winged helix transcription factor 3 (FOXP3), a factor required for development and function of Treg. P60 enters the cells, inhibits FOXP3 nuclear translocation, and reduces its ability to suppress the transcription factors NF-¿B and NFAT. In vitro, P60 inhibited murine and human-derived Treg and improved effector T cell stimulation. P60 administration to newborn mice induced a lymphoproliferative autoimmune syndrome resembling the reported pathology in scurfy mice lacking functional Foxp3. However, P60 did not cause toxic effects in adult mice and, when given to BALB/c mice immunized with the cytotoxic T cell epitope AH1 from CT26 tumor cells, it induced protection against tumor implantation. Similarly, P60 improved the antiviral efficacy of a recombinant adenovirus expressing NS3 protein from hepatitis C virus. Functional inhibition of Treg by the FOXP3-inhibitory peptide P60 constitutes a strategy to enhance antitumor and antiviral immunotherapies.