Ortiz-Espinosa, S. (Sergio)
- Publications
- item.page.relationships.isContributorAdvisorOfPublication
- item.page.relationships.isContributorOfPublication
8 results
Search Results
Now showing 1 - 8 of 8
- Potenciación de la Inmunoterapia frente al cáncer de pulmón mediante la modulación del microambiente tumoral(Universidad de Navarra, 2021-07-06) Ortiz-Espinosa, S. (Sergio); Pio, R. (Rubén); Ajona, D. (Daniel)Complement C5a has been proposed as a major regulator of myeloid-derived suppressor cells (MDSCs). In this thesis, we aimed to evaluate the mechanisms by which the C5a/C5aR1 axis endows MDSCs with properties that facilitate tumor growth and metastatic spread. Local C5a production in primary tumors seems to promote the recruitment of MDSCs, which results in a decrease in the frequency and activity of CD8 T cytotoxic lymphocytes. For this reason, we hypothesized that combined inhibition of C5a/C5aR1 and programmed cell death protein 1 (PD-1) signaling may have a synergistic antitumor effect. Using syngeneic models of lung cancer, we demonstrate that the combined blockade of C5a (AON-D21) and PD-1 (RMP1-14) markedly reduced tumor growth and led to prolonged survival. This effect was accompanied by a negative association between the frequency of CD8 T cells and MDSCs within tumors, which may result in a more complete reversal of CD8 T-cell exhaustion. This study provides support for the clinical evaluation of anti PD-1 and anti-C5a drugs as a novel combination therapeutic strategy for lung cancer. We also characterized the role of C5a on the two distinct subsets of MDSCs: polymorphonuclear MDSCs (PMN-MDSCs) and monocytic MDSCs (MON-MDSCs). Using ex vivo generated MDSCs and antagonists for C5a (AON-D21) and C5aR1 (PMX53), we demonstrate that C5a promoted an integrin-independent amoeboid mode of migration on PMN-MDSCs, while had no apparent effect on MON-MDSCs. In association with the effect on PMN-MDSC migration, C5a downregulated the expression of β1 and β3 integrins (mediators of cell-matrix adhesion) and upregulated the expression of the mediator of leukocyte extravasation CD11b. Moreover, stimulation of PMN-MDSCs with C5a favored the invasion of cancer cells via a process dependent on the extrusion of neutrophil extracellular traps (NETs). C5a/C5aR1 blockade or NET inhibition reduced the number of circulating tumor cells (CTCs) and the metastatic burden in a lung metastasis model. In support of the relevance of these findings obtained in mice, C5a was able to stimulate invasion and NETosis of PMN-MDSCs obtained from lung cancer patients. Moreover, myeloperoxidase (MPO)-DNA complexes, markers of NETosis, were elevated in lung cancer patients and correlated with C5a levels. We conclude that blockade of C5a results in a substantial improvement in the efficacy of anti PD-1 antibodies against lung cancer growth, and that C5a induces the formation of NETs by MDSCs to facilitate the dissemination, colonization and metastasis of cancer cells.
- SRC family kinase (SFK) inhibitor dasatinib improves the antitumor activity of anti-PD-1 in NSCLC models by inhibiting Treg cell conversion and proliferation(2021) Expósito, F. (Francisco); Pio, R. (Rubén); Sainz, C. (Cristina); Senent, Y. (Yaiza); Garmendia, I. (Irati); Remirez, A. (Ana); Agorreta, J. (Jackeline); Lozano-Moreda, T. (Teresa); García-Pedrero, J.M. (Juana M.); Montuenga-Badia, L.M. (Luis M.); Bertolo, C. (Cristina); Villalba-Esparza, M. (María); Redrado, M. (Miriam); Redín, E. (Esther); Andrea, C.E. (Carlos Eduardo) de; Ortiz-Espinosa, S. (Sergio); Serrano-Tejero, D. (Diego); Calvo-González, A. (Alfonso); Ajona, D. (Daniel); Lasarte, J.J. (Juan José)Introduction The use of immune-checkpoint inhibitors has drastically improved the management of patients with non-small cell lung cancer (NSCLC), but innate and acquired resistances are hurdles needed to be solved. Immunomodulatory drugs that can reinvigorate the immune cytotoxic activity, in combination with antiprogrammed cell death 1 (PD-1) antibody, are a great promise to overcome resistance. We evaluated the impact of the SRC family kinases (SFKs) on NSCLC prognosis, and the immunomodulatory effect of the SFK inhibitor dasatinib, in combination with anti-PD-1, in clinically relevant mouse models of NSCLC. Methods A cohort of patients from University Clinic of Navarra (n=116) was used to study immune infiltrates by multiplex immunofluorescence (mIF) and YES1 protein expression in tumor samples. Publicly available resources (TCGA, Km Plotter, and CIBERSORT) were used to study patient's survival based on expression of SFKs and tumor infiltrates. Syngeneic NSCLC mouse models 393P and UNSCC680AJ were used for in vivo drug testing. Results Among the SFK members, YES1 expression showed the highest association with poor prognosis. Patients with high YES1 tumor levels also showed high infiltration of CD4+/FOXP3+ cells (regulatory T cells (Tregs)), suggesting an immunosuppressive phenotype. After testing for YES1 expression in a panel of murine cell lines, 393P and UNSCC680AJ were selected for in vivo studies. In the 393P model, dasatinib+anti-PD-1 treatment resulted in synergistic activity, with 87% tumor regressions and development of immunological memory that impeded tumor growth when mice were rechallenged. In vivo depletion experiments further showed that CD8+ and CD4+ cells are necessary for the therapeutic effect of the combination. The antitumor activity was accompanied by a very significant decrease in the number of Tregs, which was validated by mIF in tumor sections. In the UNSCC680AJ model, the antitumor effects of dasatinib+anti-PD-1 were milder but similar to the 393P model. In in vitro assays, we demonstrated that dasatinib blocks proliferation and transforming growth factor beta-driven conversion of effector CD4+ cells into Tregs through targeting of phospholymphocyte-specific protein tyrosine kinase and downstream effectors pSTAT5 and pSMAD3. Conclusions YES1 protein expression is associated with increased numbers of Tregs in patients with NSCLC. Dasatinib synergizes with anti-PD-1 to impair tumor growth in NSCLC experimental models. This study provides the preclinical rationale for the combined use of dasatinib and PD-1/programmed death-ligand 1 blockade to improve outcomes of patients with NSCLC.
- Complement in metastasis: a comp in the camp(Frontiers Media SA, 2019) Pio, R. (Rubén); Ortiz-Espinosa, S. (Sergio); Lecanda, F. (Fernando); Ajona, D. (Daniel)The complement system represents a pillar of the innate immune response. This system, critical for host defense against pathogens, encompasses more than 50 soluble, and membrane-bound proteins. Emerging evidence underscores its clinical relevance in tumor progression and its role in metastasis, one of the hallmarks of cancer. The multistep process of metastasis entails the acquisition of advantageous functions required for the formation of secondary tumors. Thus, targeting components of the complement system could impact not only on tumor initiation but also on several crucial steps along tumor dissemination. This novel vulnerability could be concomitantly exploited with current strategies overcoming tumor-mediated immunosuppression to provide a substantial clinical benefit in the treatment of metastatic disease. In this review, we offer a tour d’horizon on recent advances in this area and their prospective potential for cancer treatment.
- Design and validation of a tunable inertial microfluidic system for the efficient enrichment of circulating tumor cells in blood(2022) Armendáriz, E. (Estibaliz); Pio, R. (Rubén); D'Avola, D. (Delia); Cochonneau, D. (Denis); Rodríguez-Pena, A. (Alejandro); Ruiz-Fernandez-de-Cordoba, B. (Borja); Ortiz-de-Solorzano, C. (Carlos); Cortés-Dominguez, I. (Iván); Sangro, B. (Bruno); Cornago, I. (Iñaki); Oyarbide, A. (Alvaro); Heymann, D. (Dominique); Morales-Urteaga, X. (Xabier); Ortiz-Espinosa, S. (Sergio); Lecanda, F. (Fernando); Argemí, J. (Josepmaria)The analysis of circulating tumor cells (CTCs) in blood is a powerful noninvasive alternative to conventional tumor biopsy. Inertial-based separation is a promising high-throughput, marker-free sorting strategy for the enrichment and isolation of CTCs. Here, we present and validate a double spiral microfluidic device that efficiently isolates CTCs with a fine-tunable cut-off value of 9 mu m and a separation range of 2 mu m. We designed the device based on computer simulations that introduce a novel, customized inertial force term, and provide practical fabrication guidelines. We validated the device using calibration beads, which allowed us to refine the simulations and redesign the device. Then we validated the redesigned device using blood samples and a murine model of metastatic breast cancer. Finally, as a proof of principle, we tested the device using peripheral blood from a patient with hepatocellular carcinoma, isolating more than 17 CTCs/ml, with purity/removal values of 96.03% and 99.99% of white blood cell and red blood cells, respectively. These results confirm highly efficient CTC isolation with a stringent cut-off value and better separation results than the state of the art.
- FOSL1 promotes cholangiocarcinoma via transcriptional effectors that could be therapeutically targeted(Elsevier, 2021) Banales, J.M. (Jesús M.); Arozarena, I. (Imanol); Vicent, S. (Silvestre); Vallejo-Blanco, A. (Adrián); Evert, M. (Matthias); Ruiz-Fernandez-de-Cordoba, B. (Borja); O’Dell, M. (Michael); Entrialgo-Cadierno, R. (Rodrigo); Avila, M.A. (Matías Antonio); Perugorria, M.J. (María J.); Ponz-Sarvise, M. (Mariano); Erice, O. (Oihane); Macaya, I. (Irati); Feliu, I. (Iker); Guruceaga, E. (Elizabeth); Olaizola, P. (Paula); Ortiz-Espinosa, S. (Sergio); Muggli, A. (Alexandra); Hezel, A.F. (Aram F.); Lecanda, F. (Fernando); García-Fernández-de-Barrena, M. (Maite); Calvisi, D.F. (Diego F.)Understanding the molecular mechanisms involved in cholangiocarcinoma (bile duct cancer) development and progression stands as a critical step for the development of novel therapies. Through an inter-species approach, this study provides evidence of the clinical and functional role of the transcription factor FOSL1 in cholangiocarcinoma. Moreover, we report that downstream effectors of FOSL1 are susceptible to pharmacological inhibition, thus providing new opportunities for therapeutic intervention.
- Id1 and PD-1 Combined Blockade Impairs Tumor Growth and Survival of KRAS-mutant Lung Cancer by Stimulating PD-L1 Expression and Tumor Infiltrating CD8+ T Cells(2020) Gil-Bazo, I. (Ignacio); Pio, R. (Rubén); Román, M. (Marta); Puyalto, A. (Ander); Collantes, M. (María); Lozano-Moreda, T. (Teresa); Vicent, S. (Silvestre); Garcia-Ros, D. (David); Villalba-Esparza, M. (María); Caglevic, C. (Christian); Ecay, M. (Margarita); Rodríguez-Remírez, M. (M.); Alignani, D. (Diego); Rolfo, C. (Christian); Guruceaga, E. (Elizabeth); Moreno, H. (Haritz); Andrea, C.E. (Carlos Eduardo) de; Ortiz-Espinosa, S. (Sergio); Vilalta, A. (Anna); Torregrosa, M.S. (María Soledad); Baraibar-Argota, I. (Iosune); Lopez, I. (Inés); Calvo-González, A. (Alfonso); Ajona, D. (Daniel); Oliver, A. (Ana); Lasarte, J.J. (Juan José)The use of PD-1/PD-L1 checkpoint inhibitors in advanced NSCLC is associated with longer survival. However, many patients do not benefit from PD-1/PD-L1 blockade, largely because of immunosuppression. New immunotherapy-based combinations are under investigation in an attempt to improve outcomes. Id1 (inhibitor of differentiation 1) is involved in immunosuppression. In this study, we explored the potential synergistic effect of the combination of Id1 inhibition and pharmacological PD-L1 blockade in three different syngeneic murine KRAS-mutant lung adenocarcinoma models. TCGA analysis demonstrated a negative and statistically significant correlation between PD-L1 and Id1 expression levels. This observation was confirmed in vitro in human and murine KRAS-driven lung cancer cell lines. In vivo experiments in KRAS-mutant syngeneic and metastatic murine lung adenocarcinoma models showed that the combined blockade targeting Id1 and PD-1 was more effective than each treatment alone in terms of tumor growth impairment and overall survival improvement. Mechanistically, multiplex quantification of CD3+/CD4+/CD8+ T cells and flow cytometry analysis showed that combined therapy favors tumor infiltration by CD8+ T cells, whilst in vivo CD8+ T cell depletion led to tumor growth restoration. Co-culture assays using CD8+ cells and tumor cells showed that T cells present a higher antitumor effect when tumor cells lack Id1 expression. These findings highlight that Id1 blockade may contribute to a significant immune enhancement of antitumor efficacy of PD-1 inhibitors by increasing PD-L1 expression and harnessing tumor infiltration of CD8+ T lymphocytes.
- Complementing the cancer-immunity cycle(Frontiers Media SA, 2019) Pio, R. (Rubén); Lambris, J.D. (John D.); Mantovani, A. (Alberto); Ortiz-Espinosa, S. (Sergio); Ajona, D. (Daniel)Reactivation of cytotoxic CD8+ T-cell responses has set a new direction for cancer immunotherapy. Neutralizing antibodies targeting immune checkpoint programmed cell death protein 1 (PD-1) or its ligand (PD-L1) have been particularly successful for tumor types with limited therapeutic options such as melanoma and lung cancer. However, reactivation of T cells is only one step toward tumor elimination, and a substantial fraction of patients fails to respond to these therapies. In this context, combination therapies targeting more than one of the steps of the cancer-immune cycle may provide significant benefits. To find the best combinations, it is of upmost importance to understand the interplay between cancer cells and all the components of the immune response. This review focuses on the elements of the complement system that come into play in the cancer-immunity cycle. The complement system, an essential part of innate immunity, has emerged as a major regulator of cancer immunity. Complement effectors such as C1q, anaphylatoxins C3a and C5a, and their receptors C3aR and C5aR1, have been associated with tolerogenic cell death and inhibition of antitumor T-cell responses through the recruitment and/or activation of immunosuppressive cell subpopulations such as myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), or M2 tumor-associated macrophages (TAMs). Evidence is provided to support the idea that complement blocks many of the effector routes associated with the cancer-immunity cycle, providing the rationale for new therapeutic combinations aimed to enhance the antitumor efficacy of anti-PD-1/PD-L1 checkpoint inhibitors.
- Short-term starvation reduces IGF-1 levels to sensitize lung tumors to PD-1 immune checkpoint blockade(Nature, 2020) Ajona, D. (Daniel); Ortiz-Espinosa, S. (Sergio); Lozano-Moreda, T. (Teresa); Expósito, F. (Francisco); Calvo-González, A. (Alfonso); Valencia, K. (Karmele); Redrado, M. (Miriam); Remirez, A. (Ana); Lecanda, F. (Fernando); Alignani, D. (Diego); Lasarte, J.J. (Juan José); Macaya, I. (Irati); Senent, Y. (Yaiza); Bertolo, C. (Cristina); Sainz, C. (Cristina); Gil-Bazo, I. (Ignacio); Eguren-Santamaría, I. (Iñaki); Lopez-Picazo, J.M. (José M.); Perez-Gracia, J.L. (Jose Luis); Andrea, C.E. (Carlos Eduardo) de; Vicent, S. (Silvestre); Fernandez-Sanmamed, M. (Miguel); Montuenga-Badia, L.M. (Luis M.); Pio, R. (Rubén); González, Á. (Álvaro)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.