Borras-Cuesta, F. (Francisco)
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- Carcinoembryonic antigen as a target to induce anti-tumor immune responses(Bentham science publishers, 2004) Borras-Cuesta, F. (Francisco); Huarte, E. (Eduardo); Sarobe, P. (Pablo); Lasarte, J.J. (Juan José)Identification of relevant targets for cancer therapy is a major goal in cancer research. In this field, the identification of tumor antigens has opened the possibility of inducing specific anti-tumor immune responses. Among these antigens, carcinoembryonic antigen (CEA) is especially relevant because CEA is expressed in a wide variety of adenocarcinomas such as colon, rectum, pancreas, gastric, breast, etc. The present review focuses on different strategies to induce anti-CEA immune responses. In a first group of strategies, the antigen is administered using viral and bacterial vectors expressing CEA, dendritic cells loaded with CEA protein, or dendritic cells transfected with DNA or RNA expressing CEA. A second group of strategies is based on immunizations with antigenic peptide determinants from CEA, rather than with immunogens containing the whole protein. This has been possible due to the identification of different peptide determinants from CEA, which when presented by MHC class I molecules, are recognized by T cytotoxic lymphocytes. More recently, due to the importance of CD4(+) T cells in the induction of immune responses, T helper peptides presented by MHC class II molecules have also been identified. To overcome the poor immunogenicity of CEA-derived peptide determinants, a common feature of self-antigens, their sequence has been modified to improve binding to MHC molecules or recognition by T cell receptors. Finally, in order to enhance immunization efficacy, some of these strategies have combined the administration of immunogens and cytokines or co-stimulatory molecules. Some of the immunization protocols developed are being tested in clinical trials with promising results. Thus, CEA may prove to be a valuable target antigen for the therapy of a high number of malignancies.
- Induction of potent and long-lasting CD4 and CD8 T-cell responses against hepatitis C virus by immunization with viral antigens plus poly(I:C) and anti-CD40(Elsevier masson, 2007) Dotor, J. (Javier); Zabaleta, A. (Aintzane); Borras-Cuesta, F. (Francisco); Quer, J. (Josep); Esteban, J.I. (Juan Ignacio); Prieto, J. (Jesús); Llopiz, D. (Diana); Vayreda, F. (Francesc); Sarobe, P. (Pablo); Arribillaga, L. (Laura); Lasarte, J.J. (Juan José)Development of vaccination strategies against hepatitis C virus (HCV) is of paramount importance. With this aim, we tested the ability of dendritic cell-activating reagents polyinosinic-polycytidylic acid (poly(I:C)) and anti-CD40, as adjuvants to induce T-cell responses against HCV. Immunization of mice with these adjuvants induced dendritic cell maturation in vivo. Also, joint administration of poly(I:C) and anti-CD40 plus HCV antigens had a synergistic effect on the induction of anti-HCV T-cell responses. CD4 responses displayed a Th1 cytokine profile, and CD8 responses could be induced by immunization with a minimal CD8 epitope. Addition of a low amount of NS3 protein (as a source of Th epitopes) to the immunization mixture enhanced CD8 responses, whereas immunization with higher doses of NS3 induced both CD4 and CD8 responses. Surprisingly, immunization with NS3 protein but not with CD8 epitopes was able to induce CD8 responses and able to recognize cells expressing HCV antigens endogenously. Moreover, immunization with these adjuvants activated NK cells, which in turn helped to induce Th1 responses. Finally, this combined immunization protocol afforded long-lasting T-cell responses, suggesting that this strategy may prove to be useful in vaccination and/or treatment of HCV infection.
- Peptide inhibitors of transforming growth factor-beta enhance the efficacy of antitumor immunotherapy(Wiley blackwell, 2009) Dotor, J. (Javier); Berraondo, P. (Pedro); Diaz-Valdes, N. (Nancy); Borras-Cuesta, F. (Francisco); Ruiz, M. (Marta); Aranda, F. (Fernando); Casares, N. (Noelia); Prieto, J. (Jesús); Bezunartea, J. (Jaione); Llopiz, D. (Diana); Sarobe, P. (Pablo); Lasarte, J.J. (Juan José)Transforming growth factor-beta (TGF-beta) is a cytokine with potent immunosuppressive effects and is overexpressed in many tumors. Therefore, development of molecules able to inhibit TGF-beta is of paramount importance to improve the efficacy of antitumor immunotherapy. TGF-beta inhibitor peptides P144 and P17 were combined with the administration of adjuvant molecules poly(I:C) and agonistic anti-CD40 antibodies, and their effect on the growth of E.G7-OVA established tumors and on antitumor immune response was evaluated. Tumor rejection efficacy of a single administration of adjuvants was enhanced from 15 to 70 % when combined with repeated injections of TGF-beta inhibitor peptides. Simultaneous administration of adjuvants and TGF-beta inhibitor peptides was required for maximal therapeutic efficacy. Although tumor cells produced TGF-beta, it was found that the beneficial effect of peptide administration was mainly due to the inhibition of TGF-beta produced by regulatory CD4(+)CD25(+) T cells rather than by tumor cells. The enhanced antitumor effect was accompanied by a higher activity of dendritic cells, natural killer cells and tumor antigen-specific T cells, as well as by a decrease in the number of myeloid-derived suppressor cells. In conclusion, administration of peptide inhibitors of TGF-beta in therapeutic vaccination enhances the efficacy of immunotherapy by increasing antitumor immune responses. These peptide inhibitors may have important applications for current immunotherapeutic strategies.
- Enhanced T cell responses against hepatitis C virus by ex vivo targeting of adenoviral particles to dendritic cells(Wiley Blackwell, 2011) Riezu-Boj, J.I. (José Ignacio); Zabaleta, A. (Aintzane); Silva, L. (Leyre); Cubero, M. (María); Echeverria, I. (Itziar); Borras-Cuesta, F. (Francisco); Bes, M. (Marta); Pereboev, A. (Alexander); Esteban, J.I. (Juan Ignacio); Prieto, J. (Jesús); Sarobe, P. (Pablo); Lasarte, J.J. (Juan José)Injection of dendritic cells (DCs) presenting viral proteins constitutes a promising approach to stimulate T cell immunity against hepatitis C virus (HCV). Here we describe a strategy to enhance antigen loading and immunostimulatory functions of DCs useful in the preparation of therapeutic vaccines. Incubation of murine DCs with CFm40L, an adapter molecule containing the coxsackie-adenovirus receptor fused to the ecto-domain of murine CD40L-induced DC maturation, produced high amounts of interleukin-12 and up-regulation of molecules associated with T helper 1 responses. Accordingly, targeting of an adenovirus encoding HCV NS3 protein (AdNS3) to DCs with CFm40L strongly enhanced NS3 presentation in vitro, activating interferon-γ-producing T cells. Moreover, immunization of mice with these DCs promoted strong CD4 and CD8 T cell responses against HCV NS3. CFh40L, a similar adapter molecule containing human CD40L, enhanced transduction and maturation of human monocyte-derived DCs. Comparison of DCs transduced with AdNS3 and CFh40L from patients with chronic HCV infection and healthy donors revealed similar maturation levels. More importantly, DCs from the patients induced NS3-specific responses when transduced with AdNS3 and CFh40L but not with AdNS3 alone. CONCLUSION: DCs transduced with AdNS3 and the adapter molecule CFm/h40L exhibit enhanced immunostimulatory functions, induce robust anti-HCV NS3 immunity in animals, and can induce antiviral immune responses in subjects with chronic HCV infection. This strategy may serve as therapeutic vaccination for patients with chronic hepatitis C.
- Adenoviral gene transfer of interleukin 12 into tumors synergizes with adoptive T cell therapy both at the induction and effector level(Mary Ann Liebert, 2000) Mazzolini, G. (Guillermo); Duarte, M. (Marina); Borras-Cuesta, F. (Francisco); Qian, C. (Cheng); Barajas, M. (Miguel); Melero, I. (Ignacio); Narvaiza, I. (Íñigo); Prieto, J. (Jesús); Xie, X. (Xiaoming)Tumors infected with a recombinant defective adenovirus expressing interleukin 12 (IL-12) undergo regression, associated with a cytotoxic T lymphocyte (CTL)-mediated antitumor immune response. In the present study we generated anti-CT26 CTLs by short-term coculture of CT26 cells and lymph node cells obtained from mice harboring subcutaneous CT26 tumors injected with an adenoviral vector expressing IL-12 (AdCMVIL-12), control adenovirus (AdCMVlacZ), or saline. Regression of small intrahepatic CT26 tumors in unrelated syngeneic animals was achieved with CTLs derived from mice whose subcutaneous tumors had been injected with AdCMVIL-12 but not with CTLs from the other two control groups. The necessary and sufficient effector cell population for adoptive transfer consisted of CD8+ T cells that showed anti-CT26 specificity partly directed against the AH1 epitope presented by H-2Ld. Interestingly, treatment of a subcutaneous tumor nodule with AdCMVIL-12, combined with intravenous adoptive T cell therapy with short-term CTL cultures, had a marked synergistic effect against large, concomitant live tumors. Expression of IL-12 in the liver in the vicinity of the hepatic tumor nodules, owing to spillover of the vector into the systemic circulation, appeared to be involved in the increased in vivo antitumor activity of injected CTLs. In addition, adoptive T cell therapy improved the outcome of tumor nodules transduced with suboptimal doses of AdCMVIL-12. Our data provide evidence of a strong synergy between gene transfer of IL-12 and adoptive T cell therapy. This synergy operates both at the induction and effector phases of the CTL response, thus providing a rationale for combined therapeutic strategies for human malignancies.
- Improved dendritic cell-based immunization against hepatitis C virus using peptide inhibitors of interleukin 10(Wiley blackwell, 2011) Riezu-Boj, J.I. (José Ignacio); Echeverria, I. (Itziar); Diaz-Valdes, N. (Nancy); Borras-Cuesta, F. (Francisco); Larrea, E. (Esther); Lerat, H. (Hervé); Prieto, J. (Jesús); Llopiz, D. (Diana); Sarobe, P. (Pablo); Belsue, V. (Virginia); Lopez-Sagaseta, J. (Jacinto); Manterola, L. (Lorea); Pawlotsky, J.M. (Jean-Michel); Lasarte, J.J. (Juan José)The high levels of interleukin 10 (IL-10) present in chronic hepatitis C virus (HCV) infection have been suggested as responsible for the poor antiviral cellular immune responses found in these patients. To overcome the immunosuppressive effect of IL-10 on antigen-presenting cells such as dendritic cells (DCs), we developed peptide inhibitors of IL-10 to restore DC functions and concomitantly induce efficient antiviral immune responses. Two IL-10-binding peptides (p9 and p13) were selected using a phage-displayed library and their capacity to inhibit IL-10 was assessed in a bioassay and in STAT-3 (signal transducer and activator of transcription 3) phosphorylation experiments in vitro. In cultures of human leukocytes where HCV core protein induces the production of IL-10, p13 restored the ability of plasmacytoid DC to produce interferon alpha (IFN-α) after Toll-like receptor 9 (TLR9) stimulation. Similarly, when myeloid DCs were stimulated with CD40L in the presence of HCV core, p9 enhanced IL-12 production by inhibiting HCV core-induced as well as CD40L-induced IL-10. Moreover, in vitro, p13 potentiated the effect of maturation stimuli on human and murine DC, increasing their IL-12 production and stimulatory activity, which resulted in enhanced proliferation and IFN-γ production by responding T-cells. Finally, immunization with p13-treated murine DC induced stronger anti-HCV T-cell responses not only in wildtype mice but also in HCV transgenic mice and in mice transiently expressing HCV core in the liver. CONCLUSION: These results suggest that IL-10 inhibiting peptides may have important applications to enhance anti-HCV immune responses by restoring the immunostimulatory capabilities of DC.
- Adjuvant combination and antigen targeting as a strategy to induce polyfunctional and high-avidity T-cell responses against poorly immunogenic tumors(American association for cancer research, 2011) Riezu-Boj, J.I. (José Ignacio); Diaz-Valdes, N. (Nancy); Mansilla, C. (Cristina); Borras-Cuesta, F. (Francisco); Ruiz, M. (Marta); Martinez, M. (Marta); Durantez, M. (Maika); Aranda, F. (Fernando); Prieto, J. (Jesús); Bezunartea, J. (Jaione); Llopiz, D. (Diana); Sarobe, P. (Pablo); Lasarte, J.J. (Juan José)Low antigen expression and an absence of coimmunostimulatory signals may be partly responsible for the low immunogenicity of many tumors. It may be possible to overcome this situation by defining a combination of adjuvants and antigens that can activate a high-avidity antitumor response. Using the poorly immunogenic B16-OVA melanoma cells as tumor model, we tested different combinations of adjuvants and antigens to treat established tumors. In the absence of exogenous antigens, repeated administration of the TLR7 ligand Imiquimod together with anti-CD40 agonistic antibodies activated only innate immunity, which was insufficient to reject intradermal tumors. Administering this adjuvant combination together with OVA as a tumor antigen induced T-cell responses that delayed tumor growth. However, administering a combination of anti-CD40 plus TLR3 and TLR7 ligands, together with antigen targeting to dendritic cells through TLR4, was sufficient to induce tumor rejection in 50% of mice. This response was associated with a greater activation of innate immunity and induction of high-avidity polyfunctional CD8(+) T-cell responses, which each contributed to tumor rejection. This therapy activated T-cell responses not only against OVA, which conferred protection against a rechallenge with B16-OVA cells, but also activated T-cell responses against other melanoma-associated antigens. Our findings support the concept that multiple adjuvant combination and antigen targeting may be a useful immunotherapeutic strategy against poorly immunogenic tumors.
- Polarity of immunogens: implications for vaccine design(Wiley-VCH Verlag Berlin, 1990) Borras-Cuesta, F. (Francisco); Prieto, J. (Jesús); Sarobe, P. (Pablo); Golvano, J.J. (José Javier); Gullon, A. (Arturo); Lasarte, J.J. (Juan José)Peptide constructs have been engineered consisting of amino acid sequence determinant recognized by T cells (TD) co-linearly linked to haptenic peptides. It was found that high anti-hapten antibody titers were induced after immunization with those constructs which had the TD sequence in the N-terminal position with respect to the hapten. Low or zero titers were elicited when the TD was in C-terminal position. Also, a high anti-hapten antibody titer corresponded to a low or zero anti-TD antibody titer and vice versa. These results suggest that immunogens are polar and stress the relevance of searching the more adequate position of the TD within a peptide construct when designing immunogens or synthetic peptide vaccines.
- Immunization with a tumor-associated CTL epitope plus a tumor-related or unrelated Th1 helper peptide elicits protective CTL immunity(Wiley Vch Verlag Berlin, 2001) Borras-Cuesta, F. (Francisco); Lopez-Diaz-de-Cerio, A. (Ascensión); Ruiz, M. (Marta); Casares, N. (Noelia); Melero, I. (Ignacio); Prieto, J. (Jesús); Sarobe, P. (Pablo); Lasarte, J.J. (Juan José)Immunization with cytotoxic T cell epitope SPSYVYHQF (AH1), derived from MuLV gp70 envelope protein expressed by CT26 tumor cells, does not protect BALB/c mice against challenge with CT26 tumor cells. By contrast, immunization with AH1 plus T helper peptides OVA(323-337) or SWM(106-118) eliciting Th1 and Th0 profiles, protected 83% and 33% of mice, respectively. Interestingly, immunization with AH1 plus both helper peptides reverted the efficacy to 33%. We identified the endogenous T helper peptide p(320-333) from gp70 which elicits a Th1 profile and is naturally processed. As for OVA(323-337), immunization with p(320-333) alone did not protect against tumor challenge. However, p(320-333) plus AH1 protected 89% of mice at day 10 after vaccination. Only 20% of mice vaccinated with AH1 + OVA(323-337) or AH1 + p(320-333) were protected when challenged 80 days after immunization. Treatment with OVA(323-337) or with p(320-333) around established tumors delayed tumor growth. Our results show that tumor-related as well as tumor-unrelated but strong Th1 peptides may be useful for inducing CTL responses in tumor immunotherapy.
- Helper cell-independent antitumor activity of potent CD8+ T cell epitope peptide vaccines is dependent upon CD40L(Taylor & Francis, 2013) Zabaleta, A. (Aintzane); Borras-Cuesta, F. (Francisco); Ruiz, M. (Marta); Prieto, J. (Jesús); Huarte, E. (Eduardo); Bezunartea, J. (Jaione); Llopiz, D. (Diana); Sarobe, P. (Pablo); Belsue, V. (Virginia); Lasarte, J.J. (Juan José)Peptide vaccines derived from CD8+ T-cell epitopes have shown variable efficacy in cancer patients. Thus, some peptide vaccines are capable of activating CD8+ T-cell responses, even in the absence of CD4+ T-cell epitopes or dendritic cell (DC)-activating adjuvants. However, the mechanisms underlying the clinical activity of these potent peptides are poorly understood. Using CT26 and ovalbumin-expressing B16 murine allograft tumor models, we found that the antitumor effect of helper cell-independent CD8 T-cell peptide vaccines is inhibited by the blockade of CD40 ligand (CD40L) in vivo. Furthermore, in vitro stimulation with antigenic peptides of cells derived from immunized mice induced the expression of CD40L on the surface of CD8+ T cells and fostered DC maturation, an effect that was partially inhibited by CD40L-blocking antibodies. Interestingly, CD40L blockade also inhibited CD8+ T-cell responses, even in the presence of fully mature DCs, suggesting a role for CD40L not only in promoting DC maturation but also in mediating CD8+ T-cell co-stimulation. Importantly, these potent peptides share features with bona fide CD4 epitopes, since they foster responses against less immunogenic CD8+ T-cell epitopes in a CD40L-dependent manner. The analysis of peptides used for the vaccination of cancer patients in clinical trials showed that these peptides also induce the expression of CD40L on the surface of CD8+ T cells. Taken together, these results suggest that CD40L expression induced by potent CD8+ T-cell epitopes can activate antitumor CD8+ T-cell responses, potentially amplifying the immunological responses to less immunogenic CD8+ T-cell epitopes and bypassing the requirement for CD4+ helper T cells in vaccination protocols.