Browsing by Keyword "Tumor microenvironment"
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Publication Advanced immunotherapies for glioblastoma: tumor neoantigen vaccines in combination with immunomodulators(BioMed Central (BMC), 2023-05-10) Segura-Collar, Berta; Hiller-Vallina, Sara; Dios Huerta, Olaya de; Caamaño-Moreno, Marta; Mondejar-Ruescas, Lucia; Sepulveda-Sanchez, Juan M; Gargini, Ricardo; Instituto de Salud Carlos III; Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Asociación Española Contra el Cáncer; Ministerio de Ciencia e Innovación (España)Glial-origin brain tumors, including glioblastomas (GBM), have one of the worst prognoses due to their rapid and fatal progression. From an oncological point of view, advances in complete surgical resection fail to eliminate the entire tumor and the remaining cells allow a rapid recurrence, which does not respond to traditional therapeutic treatments. Here, we have reviewed new immunotherapy strategies in association with the knowledge of the immune micro-environment. To understand the best lines for the future, we address the advances in the design of neoantigen vaccines and possible new immune modulators. Recently, the efficacy and availability of vaccine development with different formulations, especially liposome plus mRNA vaccines, has been observed. We believe that the application of new strategies used with mRNA vaccines in combination with personalized medicine (guided by different omic's strategies) could give good results in glioma therapy. In addition, a large part of the possible advances in new immunotherapy strategies focused on GBM may be key improving current therapies of immune checkpoint inhibitors (ICI), given the fact that this type of tumor has been highly refractory to ICI.Publication Autotaxin impedes anti-tumor immunity by suppressing chemotaxis and tumor infiltration of CD8+ T cells(Elsevier, 2021-11-16) Matas-Rico, Elisa; Frijlink, Elselien; van der Haar Àvila, Irene; Menegakis, Apostolos; van Zon, Maaike; Morris, Andrew J.; Koster, Jan; Salgado-Polo, Fernando; de Kivit, Sander; Lança, Telma; Mazzocca, Antonio; Johnson, Zoë; Haanen, John; Schumacher, Ton N.; Perrakis, Anastassis; Verbrugge, Inge; van den Berg, Joost H.; Borst, Jannie; Moolenaar, Wouter H.; [Matas-Rico,E; Salgado-Polo,F; Perrakis,A; Moolenaar,WH] Division of Biochemistry, Netherlands Cancer Institute, Amsterdam, the Netherlands. [Frijlink,E; van der Haar Àvila,I; de Kivit,S; Verbrugge,I; Borst,J] Division of Tumor Biology and Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands. [Frijlink,E; van der Haar Àvila,I; Menegakis,A; Salgado-Polo,F; de Kivit,S; Lança,T; Schumacher,TN; Perrakis,A; Verbrugge,I; Borst,J] Oncode Institute, Utrecht, the Netherlands. [Menegakis,A] Division of Cell Biology, Netherlands Cancer Institute, Amsterdam, the Netherlands. [van Zon,M; Lança,T; Haanen,J; Schumacher,TN; van den Berg,JH] Division of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands. [Morris,AJ] Division of Cardiovascular Medicine, Gill Heart Institute and Lexington Veterans Affairs Medical Center, University of Kentucky, Lexington, KY, USA. [Koster,J] Laboratory for Experimental Oncology and Radiobiology, Amsterdam UMC, Amsterdam, the Netherlands. [Mazzocca,A] Interdisciplinary Department of Medicine, University of Bari School of Medicine, Bari, Italy. [Johnson,Z] Onctura SA, Campus Biotech Innovation Park, Geneva, Switzerland. [Matas-Rico,E] Department of Cell Biology, Genetics and Physiology, Malaga University, Malaga, Spain. [Matas-Rico,E] Genitourinary Cancer Translational Research Group, The Institute of Biomedical Research in Malaga (IBIMA), Malaga, Spain. [van der Haar Àvila,I] Amsterdam UMC, Department of Molecular Cell Biology and Immunology, Amsterdam UMC, Amsterdam, the Netherlands. [de Kivit,S; Borst,J] Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands. [Verbrugge,I] Janssen Pharmaceutica NV, Beerse, Belgium. [van den Berg,JH] CellPoint BV, Oegstgeest, the Netherlands.Autotaxin (ATX; ENPP2) produces lysophosphatidic acid (LPA) that regulates multiple biological functions via cognate G protein-coupled receptors LPAR1-6. ATX/LPA promotes tumor cell migration and metastasis via LPAR1 and T cell motility via LPAR2, yet its actions in the tumor immune microenvironment remain unclear. Here, we show that ATX secreted by melanoma cells is chemorepulsive for tumor-infiltrating lymphocytes (TILs) and circulating CD8+ T cells ex vivo, with ATX functioning as an LPA-producing chaperone. Mechanistically, T cell repulsion predominantly involves Gα12/13-coupled LPAR6. Upon anti-cancer vaccination of tumor-bearing mice, ATX does not affect the induction of systemic T cell responses but, importantly, suppresses tumor infiltration of cytotoxic CD8+ T cells and thereby impairs tumor regression. Moreover, single-cell data from melanoma tumors are consistent with intratumoral ATX acting as a T cell repellent. These findings highlight an unexpected role for the pro-metastatic ATX-LPAR axis in suppressing CD8+ T cell infiltration to impede anti-tumor immunity, suggesting new therapeutic opportunities.Publication Cellular Plasticity and Tumor Microenvironment in Gliomas: The Struggle to Hit a Moving Target.(Multidisciplinary Digital Publishing Institute (MDPI), 2020-06-18) Gargini, Ricardo; Segura-Collar, Berta; Sánchez-Gómez, Pilar; Asociación Española Contra el Cáncer; Ministerio de Economía y Competitividad (España)Brain tumors encompass a diverse group of neoplasias arising from different cell lineages. Tumors of glial origin have been the subject of intense research because of their rapid and fatal progression. From a clinical point of view, complete surgical resection of gliomas is highly difficult. Moreover, the remaining tumor cells are resistant to traditional therapies such as radio- or chemotherapy and tumors always recur. Here we have revised the new genetic and epigenetic classification of gliomas and the description of the different transcriptional subtypes. In order to understand the progression of the different gliomas we have focused on the interaction of the plastic tumor cells with their vasculature-rich microenvironment and with their distinct immune system. We believe that a comprehensive characterization of the glioma microenvironment will shed some light into why these tumors behave differently from other cancers. Furthermore, a novel classification of gliomas that could integrate the genetic background and the cellular ecosystems could have profound implications in the efficiency of current therapies as well as in the development of new treatments.Publication Immune Landscape in Tumor Microenvironment: Implications for Biomarker Development and Immunotherapy(Multidisciplinary Digital Publishing Institute (MDPI), 2020-08) Pérez-Romero, Karim; Rodriguez, Ramon M; Amedei, Amedeo; Barcelo-Coblijn, Gwendolyn; Lopez, Daniel HIntegration of the tumor microenvironment as a fundamental part of the tumorigenic process has undoubtedly revolutionized our understanding of cancer biology. Increasing evidence indicates that neoplastic cells establish a dependency relationship with normal resident cells in the affected tissue and, furthermore, develop the ability to recruit new accessory cells that aid tumor development. In addition to normal stromal and tumor cells, this tumor ecosystem includes an infiltrated immune component that establishes complex interactions that have a critical effect during the natural history of the tumor. The process by which immune cells modulate tumor progression is known as immunoediting, a dynamic process that creates a selective pressure that finally leads to the generation of immune-resistant cells and the inability of the immune system to eradicate the tumor. In this context, the cellular and functional characterization of the immune compartment within the tumor microenvironment will help to understand tumor progression and, ultimately, will serve to create novel prognostic tools and improve patient stratification for cancer treatment. Here we review the impact of the immune system on tumor development, focusing particularly on its clinical implications and the current technologies used to analyze immune cell diversity within the tumor.Publication Immune Profiling of Gliomas Reveals a Connection with IDH1/2 Mutations, Tau Function and the Vascular Phenotype.(Multidisciplinary Digital Publishing Institute (MDPI), 2020-11-02) Cejalvo, Teresa; Gargini, Ricardo; Segura-Collar, Berta; Mata-Martínez, Pablo; Herranz, Beatriz; Cantero, Diana; Ruano, Yolanda; García-Pérez, Daniel; Pérez-Núñez, Ángel; Ramos, Ana; Hernández-Laín, Aurelio; Martín-Soberón, María Cruz; Sánchez-Gómez, Pilar; Sepúlveda-Sánchez, Juan Manuel; Ministerio de Economía y Competitividad (España); Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Asociación Española Contra el Cáncer; Ministerio de Ciencia, Innovación y Universidades (España); Fundación Sociedad Española de Oncología MédicaGliomas remain refractory to all attempted treatments, including those using immune checkpoint inhibitors. The characterization of the tumor (immune) microenvironment has been recognized as an important challenge to explain this lack of response and to improve the therapy of glial tumors. We designed a prospective analysis of the immune cells of gliomas by flow cytometry. Tumors with or without isocitrate dehydrogenase 1/2 (IDH1/2) mutations were included in the study. The genetic profile and the presence of different molecular and cellular features of the gliomas were analyzed in parallel. The findings were validated in syngeneic mouse models. We observed that few immune cells infiltrate mutant IDH1/2 gliomas whereas the immune content of IDH1/2 wild-type tumors was more heterogeneous. Some of them contained an important immune infiltrate, particularly enriched in myeloid cells with immunosuppressive features, but others were more similar to mutant IDH1/2 gliomas, with few immune cells and a less immunosuppressive profile. Notably, we observed a direct correlation between the percentage of leukocytes and the presence of vascular alterations, which were associated with a reduced expression of Tau, a microtubule-binding protein that controls the formation of tumor vessels in gliomas. Furthermore, overexpression of Tau was able to reduce the immune content in orthotopic allografts of GL261 cells, delaying tumor growth. We have confirmed the reduced infiltration of immune cells in IDH1/2 mutant gliomas. By contrast, in IDH1/2 wild-type gliomas, we have found a direct correlation between the presence of vascular alterations and the entrance of leukocytes into the tumors. Interestingly, high levels of Tau inversely correlated with the vascular and the immune content of gliomas. Altogether, our results could be exploited for the design of more successful clinical trials with immunomodulatory molecules.Publication Organotypic Brain Cultures for Metastasis Research(Nature Publishing Group, 2021) Zhu, Lucia; Valiente, ManuelPublication Targeting galectin-1 inhibits pancreatic cancer progression by modulating tumor-stroma crosstalk(National Academy of Sciences, 2018-04-17) Orozco, Carlos A; Martinez-Bosch, Neus; Guerrero, Pedro E; Vinaixa, Judith; Dalotto-Moreno, Tomás; Iglesias, Mar; Moreno, Mireia; Djurec, Magdolna; Poirier, Françoise; Gabius, Hans-Joachim; Fernandez-Zapico, Martin E; Hwang, Rosa F; Guerra, Carmen; Rabinovich, Gabriel A; Navarro, Pilar; Ministerio de Economía y Competitividad (España); Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Asociación Española de Pancreatologia; Government of Catalonia (España); Colciencias; University of Buenos Aires (Argentina); Sales Foundation; Bunge and Born Foundation; National Scientific and Technical Research Council (Argentina)Pancreatic ductal adenocarcinoma (PDA) remains one of the most lethal tumor types, with extremely low survival rates due to late diagnosis and resistance to standard therapies. A more comprehensive understanding of the complexity of PDA pathobiology, and especially of the role of the tumor microenvironment in disease progression, should pave the way for therapies to improve patient response rates. In this study, we identify galectin-1 (Gal1), a glycan-binding protein that is highly overexpressed in PDA stroma, as a major driver of pancreatic cancer progression. Genetic deletion of Gal1 in a Kras-driven mouse model of PDA (Ela-KrasG12Vp53 -/- ) results in a significant increase in survival through mechanisms involving decreased stroma activation, attenuated vascularization, and enhanced T cell infiltration leading to diminished metastasis rates. In a human setting, human pancreatic stellate cells (HPSCs) promote cancer proliferation, migration, and invasion via Gal1-driven pathways. Moreover, in vivo orthotopic coinjection of pancreatic tumor cells with Gal1-depleted HPSCs leads to impaired tumor formation and metastasis in mice. Gene-expression analyses of pancreatic tumor cells exposed to Gal1 reveal modulation of multiple regulatory pathways involved in tumor progression. Thus, Gal1 hierarchically regulates different events implicated in PDA biology including tumor cell proliferation, invasion, angiogenesis, inflammation, and metastasis, highlighting the broad therapeutic potential of Gal1-specific inhibitors, either alone or in combination with other therapeutic modalities.Publication TGF-β-induced IGFBP-3 is a key paracrine factor from activated pericytes that promotes colorectal cancer cell migration and invasion.(2020-08-07) Navarro, Rocío; Tapia-Galisteo, Antonio; Martín-García, Laura; Tarín, Carlos; Corbacho, Cesáreo; Sánchez-Tirado, Esther; Campuzano, Susana; González-Cortés, Araceli; Yáñez-Sedeño, Paloma; Compte, Marta; Sanz, Laura; Tapia‐Galisteo, Antonio; Martín‐García, Laura; Gómez-López, Gonzalo; Sánchez‐Tirado, Esther; González‐Cortés, Araceli; Yáñez‐Sedeño, Paloma; Álvarez-Vallina, Luis; Unión Europea. Comisión Europea. European Research Council (ERC); Instituto de Salud Carlos III; Comunidad de Madrid (España); Ministerio de Economía y Competitividad (España)The crosstalk between cancer cells and the tumor microenvironment has been implicated in cancer progression and metastasis. Fibroblasts and immune cells are widely known to be attracted to and modified by cancer cells. However, the role of pericytes in the tumor microenvironment beyond endothelium stabilization is poorly understood. Here, we report that pericytes promoted colorectal cancer (CRC) cell proliferation, migration, invasion, stemness, and chemoresistance in vitro, as well as tumor growth in a xenograft CRC model. We demonstrate that coculture with human CRC cells induced broad transcriptomic changes in pericytes, mostly associated with TGF-β receptor activation. The prognostic value of a TGF-β response signature in pericytes was analyzed in CRC patient data sets. This signature was found to be a good predictor of CRC relapse. Moreover, in response to stimulation by CRC cells, pericytes expressed high levels of TGF-β1, initiating an autocrine activation loop. Investigation of secreted mediators and underlying molecular mechanisms revealed that IGFBP-3 is a key paracrine factor from activated pericytes affecting CRC cell migration and invasion. In summary, we demonstrate that the interplay between pericytes and CRC cells triggers a vicious cycle that stimulates pericyte cytokine secretion, in turn increasing CRC cell tumorigenic properties. Overall, we provide another example of how cancer cells can manipulate the tumor microenvironment.