Aranda, F. (Fernando)
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- Mouse Models of Peritoneal Carcinomatosis to Develop Clinical Applications(2021) Berraondo, P. (Pedro); Cirella, A. (Assunta); Fernández-Sendín, M. (Myriam); Bella-Carreño, Á. (Ángela); Di-Trani, C.A. (Claudia Augusta); Aranda, F. (Fernando); Arrizabalaga, L. (Leire); Melero, I. (Ignacio); Medina-Echeverz, J. (José); Teijeira, A. (Álvaro)Simple Summary Peritoneal carcinomatosis mouse models as a platform to test, improve and/or predict the appropriate therapeutic interventions in patients are crucial to providing medical advances. Here, we overview reported mouse models to explore peritoneal carcinomatosis in translational biomedical research. Peritoneal carcinomatosis of primary tumors originating in gastrointestinal (e.g., colorectal cancer, gastric cancer) or gynecologic (e.g., ovarian cancer) malignancies is a widespread type of tumor dissemination in the peritoneal cavity for which few therapeutic options are available. Therefore, reliable preclinical models are crucial for research and development of efficacious treatments for this condition. To date, a number of animal models have attempted to reproduce as accurately as possible the complexity of the tumor microenvironment of human peritoneal carcinomatosis. These include: Syngeneic tumor cell lines, human xenografts, patient-derived xenografts, genetically induced tumors, and 3D scaffold biomimetics. Each experimental model has its own strengths and limitations, all of which can influence the subsequent translational results concerning anticancer and immunomodulatory drugs under exploration. This review highlights the current status of peritoneal carcinomatosis mouse models for preclinical development of anticancer drugs or immunotherapeutic agents.
- 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.
- Multifaceted effects of soluble human CD6 in experimental cancer models(2020) Orta-Mascaró, M. (Marc); González-Aseguinolaza, G. (Gloria); Consuegra-Fernández, M. (Marta); Velasco-de-Andrés, M. (Maria); Martínez, V. (Vanessa); Lozano, F. (Francisco); Carreras, E. (Esther); Simões, I.T. (Inês T.); Català, C. (Crisitna); Aranda, F. (Fernando); Merino, R. (Ramón); Alberola-Ila, J. (José); Álvarez, P. (Pilar); Casadó-Llombart, S. (Sergi); Merino, J. (Jesús)Background CD6 is a lymphocyte surface co-receptor physically associated with the T-cell receptor (TCR)/CD3 complex at the center of the immunological synapse. There, CD6 assists in cell-to-cell contact stabilization and modulation of activation/differentiation events through interaction with CD166/ALCAM (activated leukocyte cell adhesion molecule), its main reported ligand. While accumulating evidence is attracting new interest on targeting CD6 for therapeutic purposes in autoimmune disorders, little is known on its potential in cancer. In an attempt to elucidate the in vivo relevance of blocking CD6- mediated interactions in health and disease, we explored the consequences of expressing high circulating levels of a soluble form CD6 (sCD6) as a decoy receptor. Methods High sCD6 serum levels were achieved by using transgenic C57BL/6 mice expressing human sCD6 under the control of lymphoid-specific transcriptional elements (shCD6LckEμTg) or wild type either transduced with hepatotropic adeno-associated virus coding for mouse sCD6 or undergoing repeated infusions of recombinant human sCD6 protein. Characterization of sCD6-induced changes was performed by ex vivo flow cytometry and functional analyses of mouse lymphoid organ cells. The in vivo relevance of those changes was explored by challenging mice with subcutaneous or metastatic tumors induced by syngeneic cancer cells of different lineage origins. Results Through a combination of in vitro and in vivo studies, we show that circulating sCD6 expression induces defective regulatory T cell (Treg) generation and function, decreased CD166/ALCAM-mediated tumor cell proliferation/migration and impaired galectin-induced T-cell apoptosis, supporting the fact that sCD6 modulates antitumor lymphocyte effector function and tumorigenesis. Accordingly, sCD6 expression in vivo resulted in delayed subcutaneous tumor growth and/or reduced metastasis on challenge of mice with syngeneic cancer cells. Conclusions Evidence is provided for the disruption of CD6 receptor–ligand interactions as a feasible immunomodulatory approach in cancer.
- 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.
- Induction of monocyte chemoattractant protein-1 and interleukin-10 by TGFbeta1 in melanoma enhances tumor infiltration and immunosuppression(American Association for Cancer Research, 2011) Riezu-Boj, J.I. (José Ignacio); Dotor, J. (Javier); Diaz-Valdes, N. (Nancy); Borras-Cuesta, F. (Francisco); Aranda, F. (Fernando); Basagoiti, M. (María); Sarobe, P. (Pablo); Monreal, I. (Iñaki); Feijoo, E. (Esperanza)Melanoma progression is associated with the expression of different growth factors, cytokines, and chemokines. Because TGFβ1 is a pleiotropic cytokine involved not only in physiologic processes but also in cancer development, we analyzed in A375 human melanoma cells, the effect of TGFβ1 on monocyte chemoattractant protein-1 (MCP-1) and interleukin-10 (IL-10) expression, two known factors responsible for melanoma progression. TGFβ1 increased the expression of MCP-1 and IL-10 in A375 cells, an effect mediated by the cross-talk between Smad, PI3K (phosphoinositide 3-kinase)/AKT, and BRAF-MAPK (mitogen activated protein kinase) signaling pathways. Supernatants from TGFβ1-treated A375 cells enhanced MCP-1-dependent migration of monocytes, which, in turn, expressed high levels of TGF,β1, bFGF, and VEGF mRNA. Moreover, these supernatants also inhibited functional properties of dendritic cells through IL-10-dependent mechanisms. When using in vitro, the TGFβ1-blocking peptide P144, TGFβ1-dependent Smad3 phosphorylation, and expression of MCP-1 and IL-10 were inhibited. In vivo, treatment of A375 tumor-bearing athymic mice with P144 significantly reduced tumor growth, associated with a lower macrophage infiltrate and decreased intratumor MCP-1 and VEGF levels, as well as angiogenesis. Finally, in C57BL/6 mice with B16-OVA melanoma tumors, when administered with immunotherapy, P144 decreased tumor growth and intratumor IL-10 levels, linked to enhanced activation of dendritic cells and natural killer cells, as well as anti-OVA T-cell responses. These results show new effects of TGFβ1 on melanoma cells, which promote tumor progression and immunosuppression, strongly reinforcing the relevance of this cytokine as a molecular target in melanoma.
- Soluble CD5 and CD6: Lymphocytic class I scavenger receptors as immunotherapeutic agents(MDPI AG, 2020) Velasco-de-Andrés, M. (Maria); Leyton-Pereira, A. (Alejandra); Català, C. (Crisitna); Aranda, F. (Fernando); Lozano, F.S. (Francisco S.); Casadó-Llombart, S. (Sergi)CD5 and CD6 are closely related signal-transducing class I scavenger receptors mainly expressed on lymphocytes. Both receptors are involved in the modulation of the activation and differentiation cell processes triggered by clonotypic antigen-specific receptors present on T and B cells (TCR and BCR, respectively). To serve such a relevant immunomodulatory function, the extracellular region of CD5 and CD6 interacts with soluble and/or cell-bound endogenous counterreceptors but also microbial-associated molecular patterns (MAMPs). Evidence from genetically-modified mouse models indicates that the absence or blockade of CD5- and CD6-mediated signals results in dysregulated immune responses, which may be deleterious or advantageous in some pathological conditions, such as infection, cancer or autoimmunity. Bench to bedside translation from transgenic data is constrained by ethical concerns which can be overcome by exogenous administration of soluble proteins acting as decoy receptors and leading to transient “functional knockdown”. This review gathers information currently available on the therapeutic efficacy of soluble CD5 and CD6 receptor infusion in different experimental models of disease. The existing proof-of-concept warrants the interest of soluble CD5 and CD6 as safe and efficient immunotherapeutic agents in diverse and relevant pathological conditions.
- Harnessing high density lipoproteins to block transforming growth factor beta and to inhibit the growth of liver tumor metastases(Public Library of Science, 2014-05) Dotor, J. (Javier); Berraondo, P. (Pedro); Gomar, C. (Celia); Diaz-Valdes, N. (Nancy); Frank, K. (Kathrin); Umansky, V. (Viktor); Aranda, F. (Fernando); Ardaiz, N. (Nuria); Prieto, J. (Jesús); Medina-Echeverz, J. (José); Fioravanti, J. (Jessica)Transforming growth factor β (TGF-β) is a powerful promoter of cancer progression and a key target for antitumor therapy. As cancer cells exhibit active cholesterol metabolism, high density lipoproteins (HDLs) appear as an attractive delivery system for anticancer TGFβ-inhibitory molecules. We constructed a plasmid encoding a potent TGF-β-blocking peptide (P144) linked to apolipoprotein A-I (ApoA-I) through a flexible linker (pApoLinkerP144). The ApoLinkerP144 sequence was then incorporated into a hepatotropic adeno-associated vector (AAVApoLinkerP144). The aim was to induce hepatocytes to produce HDLs containing a modified ApoA-I capable of blocking TGF-β. We observed that transduction of the murine liver with pApoLinkerP144 led to the appearance of a fraction of circulating HDL containing the fusion protein. These HDLs were able to attenuate TGF-β signaling in the liver and to enhance IL-12 -mediated IFN-γ production. Treatment of liver metastasis of MC38 colorectal cancer with AAVApoLinkerP144 resulted in a significant reduction of tumor growth and enhanced expression of IFN-γ and GM-CSF in cancerous tissue. ApoLinkerP144 also delayed MC38 liver metastasis in Rag2-/-IL2rγ-/- immunodeficient mice. This effect was associated with downregulation of TGF-β target genes essential for metastatic niche conditioning. Finally, in a subset of ret transgenic mice, a model of aggressive spontaneous metastatic melanoma, AAVApoLinkerP144 delayed tumor growth in association with increased CD8+ T cell numbers in regional lymph nodes. In conclusion, modification of HDLs to transport TGF-β-blocking molecules is a novel and promising approach to inhibit the growth of liver metastases by immunological and non-immunological mechanisms.
- Combinación de adyuvantes y bloqueo de mecanismos inmunosupresores como estrategias de vacunación terapéutica(Universidad de Navarra, 2013-03-27) Aranda, F. (Fernando); Sarobe, P. (Pablo)La activación de linfocitos T efectores capaces de reconocer a las células malignas que expresan antígenos tumorales podría dar lugar a nuevas estrategias de inmunoterapia para la eliminación tumoral. Sin embargo, la conversión de linfocitos T naive en efectores se encuentra dificultada por la pobre inmunogenicidad de los tumores, caracterizados por su baja expresión antigénica y la ausencia de señales inmunoestimuladoras que activen a las células presentadoras de antígeno (CPA). Por ello, la caracterización de una combinación de antígenos y adyuvantes que superen esta situación y activen respuestas antitumorales eficaces es un importante objetivo. Usando el melanoma B16-OVA como modelo de tumor poco inmunogénico, hemos ensayado diferentes combinaciones de antígeno y adyuvantes para el tratamiento de tumores establecidos. Sin la inclusión de antígenos tumorales exógenos, la administración del ligando de TLR7 Imiquimod y anticuerpos agonistas anti-CD40 activó solamente la inmunidad innata, que no rechazó los tumores. La administración de esta combinación de adyuvantes junto con OVA como antígeno tumoral indujo respuestas de linfocitos T que retrasaron el crecimiento tumoral pero no indujeron su rechazo. Sin embargo, el tratamiento con una combinación de los adyuvantes anti-CD40 y ligandos de TLR3 y TLR7 junto con el antígeno vehiculizado a las células dendríticas a través de TLR4, indujo el rechazo tumoral en el 50% de los animales. Esto se asoció a una mejor activación de la inmunidad innata y a la inducción de linfocitos T CD8+ polifuncionales de alta avidez, responsables del rechazo tumoral. Esta terapia activó no sólo respuestas frente a OVA, proporcionando protección futura frente al propio tumor, sino también respuestas frente a otros antígenos asociados al melanoma, que protegieron frente al tumor parental B16-F10. Estos resultados sugieren que una combinación múltiple de adyuvantes y la vehiculización del antígeno podría ser una estrategia útil en la inmunoterapia de tumores poco inmunogénicos. Junto a la baja inmunogenicidad intrínseca de las células tumorales, existen otros mecanismos inmunosupresores que llevan a la evasión el reconocimiento inmune o a la desactivación de los mecanismos efectores de células T anti-tumorales. Entre los mecanismos mejor caracterizados están las citoquinas inmunosupresoras, IL-10 y el TGF-beta, lo que ha sugerido que su inhibición podría tener un efecto beneficioso en las fases de activación y efectoras de la respuesta antitumoral. Mediante la combinación de las estrategias de vacunación mencionadas anteriormente con péptidos inhibidores y anticuerpos monoclonales bloqueantes de estas citoquinas hemos potenciado la respuesta inmunitaria frente a los antígenos tumorales. Esto ha supuesto que en el modelo de B16-OVA la combinación múltiple de adyuvantes junto con el bloqueo de IL-10 sea capaz de rechazar el 100% de los tumores.
- Vaccine-induced but not tumor-derived Interleukin-10 dictates the efficacy of Interleukin-10 blockade in therapeutic vaccination(Taylor & Francis, 2015) Infante, S. (Stefany); Diaz-Valdes, N. (Nancy); Ruiz, M. (Marta); Aranda, F. (Fernando); Llopiz, D. (Diana); Sarobe, P. (Pablo); Belsue, V. (Virginia); Lasarte, J.J. (Juan José)Blocking antibodies against immunosuppressive molecules have shown promising results in cancer patients. However, there are not enough data to define those conditions dictating treatment efficacy. In this scenario, IL-10 is a cytokine with controversial effects on tumor growth. Thus, our aim was to characterize in which setting IL-10 blockade may potentiate the beneficial effects of a therapeutic vaccine In the IL-10-expressing B16-OVA and TC-1 P3 (A15) tumor models, therapeutic vaccination with tumor antigens plus the TLR7 ligand Imiquimod increased IL-10 production. Although blockade of IL-10 signal with anti-IL-10R antibodies did not inhibit tumor growth, when combined with vaccination it enhanced tumor rejection, associated with stronger innate and adaptive immune responses. Interestingly, a similar enhancement on immune responses was observed after simultaneous vaccination and IL-10 blockade in naive mice. However, when using vaccines containing as adjuvants the TLR3 ligand poly(I:C) or anti-CD40 agonistic antibodies, despite tumor IL-10 expression, anti-IL-10R antibodies did not provide any beneficial effect on tumor growth and antitumor immune responses. Of note, as opposed to Imiquimod, vaccination with this type of adjuvants did not induce IL-10 and correlated with a lack of in vitro IL-10 production by dendritic cells (DC). Finally, in B16-OVA-bearing mice, blockade of IL-10 during therapeutic vaccination with a multiple adjuvant combination (MAC) with potent immunostimulatory properties but still inducing IL-10 led to superior antitumor immunity and complete tumor rejection. These results suggest that for therapeutic antitumor vaccination, blockade of vaccine-induced IL-10 is more relevant than tumorassociated IL-10.
- Intratumoral co-injection of the poly I:C-derivative BO-112 and a STING agonist synergize to achieve local and distant anti-tumor efficacy(2021) Glez-Vaz, J. (Javier); Berraondo, P. (Pedro); Fan, X. (X.); Fernández-Sendín, M. (Myriam); de Andrea, C. E. (Carlos E.); González-Gomariz, J. (José); Rodriguez-Ruiz, M.E. (María Esperanza); Villalba, M. (María); Quintero, M. (Marisol); Aranda, F. (Fernando); Molina, C. (Carmeen); Ochoa, M.C. (María Carmen); Melero, I. (Ignacio); Álvarez, M. (Maite); Shen, W. H. (Wen H.); Fernandez-Sanmamed, M. (Miguel); Teijeira, A. (Álvaro)Background BO-112 is a nanoplexed form of polyinosinic:polycytidylic acid that acting on toll-like receptor 3 (TLR3), melanoma differentiation-associated protein 5 (MDA5) and protein kinase RNA-activated (PKR) elicits rejection of directly injected transplanted tumors, but has only modest efficacy against distant untreated tumors. Its clinical activity has also been documented in early phase clinical trials. The 5,6-dimethylxanthenone-4-acetic acid (DMXAA) stimulator of interferon genes (STING) agonist shows a comparable pattern of efficacy when used via intratumoral injections. Methods Mice subcutaneously engrafted with bilateral MC38 and B16.OVA-derived tumors were treated with proinflammatory immunotherapy agents known to be active when intratumorally delivered. The combination of BO-112 and DMXAA was chosen given its excellent efficacy and the requirements for antitumor effects were studied on selective depletion of immune cell types and in gene-modified mouse strains lacking basic leucine zipper ATF-like transcription factor 3 (BATF3), interferon-α/β receptor (IFNAR) or STING. Spatial requirements for the injections were studied in mice bearing three tumor lesions. Results BO-112 and DMXAA when co-injected in one of the lesions of mice bearing concomitant bilateral tumors frequently achieved complete local and distant antitumor efficacy. Synergistic effects were contingent on CD8 T cell lymphocytes and dependent on conventional type 1 dendritic cells, responsiveness to type I interferon (IFN) and STING function in the tumor-bearing host. Efficacy was preserved even if BO-112 and DMXAA were injected in separate lesions in a manner able to control another untreated third-party tumor. Efficacy could be further enhanced on concurrent PD-1 blockade. Conclusion Clinically feasible co-injections of BO-112 and a STING agonist attain synergistic efficacy able to eradicate distant untreated tumor lesions.