Browsing by MeSH term "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 An update on the molecular biology of glioblastoma, with clinical implications and progress in its treatment.(2022-09-21) Verdugo, Elena; Puerto, Iker; Medina, Miguel ÁngelGlioblastoma multiforme (GBM) is the most aggressive and common malignant primary brain tumor. Patients with GBM often have poor prognoses, with a median survival of ∼15 months. Enhanced understanding of the molecular biology of central nervous system tumors has led to modifications in their classifications, the most recent of which classified these tumors into new categories and made some changes in their nomenclature and grading system. This review aims to give a panoramic view of the last 3 years' findings in glioblastoma characterization, its heterogeneity, and current advances in its treatment. Several molecular parameters have been used to achieve an accurate and personalized characterization of glioblastoma in patients, including epigenetic, genetic, transcriptomic and metabolic features, as well as age- and sex-related patterns and the involvement of several noncoding RNAs in glioblastoma progression. Astrocyte-like neural stem cells and outer radial glial-like cells from the subventricular zone have been proposed as agents involved in GBM of IDH-wildtype origin, but this remains controversial. Glioblastoma metabolism is characterized by upregulation of the PI3K/Akt/mTOR signaling pathway, promotion of the glycolytic flux, maintenance of lipid storage, and other features. This metabolism also contributes to glioblastoma's resistance to conventional therapies. Tumor heterogeneity, a hallmark of GBM, has been shown to affect the genetic expression, modulation of metabolic pathways, and immune system evasion. GBM's aggressive invasion potential is modulated by cell-to-cell crosstalk within the tumor microenvironment and altered expressions of specific genes, such as ANXA2, GBP2, FN1, PHIP, and GLUT3. Nevertheless, the rising number of active clinical trials illustrates the efforts to identify new targets and drugs to treat this malignancy. Immunotherapy is still relevant for research purposes, given the amount of ongoing clinical trials based on this strategy to treat GBM, and neoantigen and nucleic acid-based vaccines are gaining importance due to their antitumoral activity by inducing the immune response. Furthermore, there are clinical trials focused on the PI3K/Akt/mTOR axis, angiogenesis, and tumor heterogeneity for developing molecular-targeted therapies against GBM. Other strategies, such as nanodelivery and computational models, may improve the drug pharmacokinetics and the prognosis of patients with GBM.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 Brain metastasis.(Nature Publishing Group, 2020-01-20) Boire, Adrienne; Brastianos, Priscilla K; Garzia, Livia; Valiente, Manuel; Ministerio de Economía y Competitividad (España); Bristol-Myers Squibb; Beug Foundation for Metastasis Research; Fundación Ramón Areces; Worldwide Cancer Research; Unión Europea. Comisión Europea. H2020; Cancer Research Institute (CRI). Clinic & Laboratory Integration Program (CLIP); Asociación Española Contra el Cáncer; European Molecular Biology Organization; Canadian Institutes of Health Research; Terry Fox Research Institute; Canadian Cancer Society Research Institute; C17 Research NetworkBrain metastasis, which commonly arises in patients with lung cancer, breast cancer and melanoma, is associated with poor survival outcomes and poses distinct clinical challenges. The brain microenvironment, with its unique cell types, anatomical structures, metabolic constraints and immune environment, differs drastically from microenvironments of extracranial lesions, imposing a distinct and profound selective pressure on tumour cells that, in turn, shapes the metastatic process and therapeutic responses. Accordingly, the study of brain metastasis could uncover new therapeutic targets and identify novel treatment approaches to address the unmet clinical need. Moreover, such efforts could provide insight into the biology of primary brain tumours, which face similar challenges to brain metastases of extracranial origin, and vice versa. However, the paucity of robust preclinical models of brain metastasis has severely limited such investigations, underscoring the importance of developing improved experimental models that holistically encompass the metastatic cascade and/or brain microenvironment. In this Viewpoint, we asked four leading experts to provide their opinions on these important aspects of brain metastasis biology and management.Publication DNGR-1 limits Flt3L-mediated antitumor immunity by restraining tumor-infiltrating type I conventional dendritic cells.(BMJ Publishing Group, 2021-05) Cueto, Francisco J; Del Fresno, Carlos; Brandi, Paola; Combes, Alexis J; Hernández-García, Elena; Sánchez-Paulete, Alfonso R; Enamorado, Michel; Bromley, Christian P; Gomez, Manuel J; Conde-Garrosa, Ruth; Mañes, Santos; Zelenay, Santiago; Melero, Ignacio; Iborra, Salvador; Krummel, Matthew F; Sancho, David; Fundación La Caixa; Asociación Española Contra el Cáncer; Instituto de Salud Carlos III; NIHR - Manchester Biomedical Research Centre (Reino Unido); Unión Europea. Comisión Europea. European Research Council (ERC); Unión Europea. Comisión Europea; Ministerio de Ciencia e Innovación (España); Agencia Estatal de Investigación (España); Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Comunidad de Madrid (España); Fondation ACTERIA (Acting on European Research in Immunology and Allergology); Atresmedia; Fundación La Marató TV3; Fundación ProCNIC; Ministerio de Ciencia e Innovación. Centro de Excelencia Severo Ochoa (España)Conventional type 1 dendritic cells (cDC1s) are central to antitumor immunity and their presence in the tumor microenvironment associates with improved outcomes in patients with cancer. DNGR-1 (CLEC9A) is a dead cell-sensing receptor highly restricted to cDC1s. DNGR-1 has been involved in both cross-presentation of dead cell-associated antigens and processes of disease tolerance, but its role in antitumor immunity has not been clarified yet. B16 and MC38 tumor cell lines were inoculated subcutaneously into wild-type (WT) and DNGR-1-deficient mice. To overexpress Flt3L systemically, we performed gene therapy through the hydrodynamic injection of an Flt3L-encoding plasmid. To characterize the immune response, we performed flow cytometry and RNA-Seq of tumor-infiltrating cDC1s. Here, we found that cross-presentation of tumor antigens in the steady state was DNGR-1-independent. However, on Flt3L systemic overexpression, tumor growth was delayed in DNGR-1-deficient mice compared with WT mice. Of note, this protection was recapitulated by anti-DNGR-1-blocking antibodies in mice following Flt3L gene therapy. This improved antitumor immunity was associated with Batf3-dependent enhanced accumulation of CD8+ T cells and cDC1s within tumors. Mechanistically, the deficiency in DNGR-1 boosted an Flt3L-induced specific inflammatory gene signature in cDC1s, including Ccl5 expression. Indeed, the increased infiltration of cDC1s within tumors and their protective effect rely on CCL5/CCR5 chemoattraction. Moreover, FLT3LG and CCL5 or CCR5 gene expression signatures correlate with an enhanced cDC1 signature and a favorable overall survival in patients with cancer. Notably, cyclophosphamide elevated serum Flt3L levels and, in combination with the absence of DNGR-1, synergized against tumor growth. DNGR-1 limits the accumulation of tumor-infiltrating cDC1s promoted by Flt3L. Thus, DNGR-1 blockade may improve antitumor immunity in tumor therapy settings associated to high Flt3L expression.Publication Dual-labeled nanoparticles based on small extracellular vesicles for tumor detection.(BioMed Central (BMC), 2022-11-14) Santos-Coquillat, Ana; Herreros-Pérez, Desiré; Samaniego, Rafael; González, María Isabel; Cussó, Lorena; Desco, Manuel; Salinas, Beatriz; Ministerio de Ciencia e Innovación (España); Instituto de Salud Carlos III; Comunidad de Madrid (España); Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Agencia Estatal de Investigación (España); Unión Europea. Fondo Social Europeo (ESF/FSE); Fundación BBVA; Fundación Ramón Areces; Instituto de Investigación Sanitaria Gregorio MarañónSmall extracellular vesicles (sEVs) are emerging natural nanoplatforms in cancer diagnosis and therapy, through the incorporation of signal components or drugs in their structure. However, for their translation into the clinical field, there is still a lack of tools that enable a deeper understanding of their in vivo pharmacokinetics or their interactions with the cells of the tumor microenvironment. In this study, we have designed a dual-sEV probe based on radioactive and fluorescent labeling of goat milk sEVs. The imaging nanoprobe was tested in vitro and in vivo in a model of glioblastoma. In vitro assessment of the uptake of the dual probe in different cell populations (RAW 264.7, U87, and HeLa) by optical and nuclear techniques (gamma counter, confocal imaging, and flow cytometry) revealed the highest uptake in inflammatory cells (RAW 264.7), followed by glioblastoma U87 cells. In vivo evaluation of the pharmacokinetic properties of nanoparticles confirmed a blood circulation time of ~ 8 h and primarily hepatobiliary elimination. The diagnostic capability of the dual nanoprobe was confirmed in vivo in a glioblastoma xenograft model, which showed intense in vivo uptake of the SEV-based probe in tumor tissue. Histological assessment by confocal imaging enabled quantification of tumor populations and confirmed uptake in tumor cells and tumor-associated macrophages, followed by cancer-associated fibroblasts and endothelial cells. We have developed a chemical approach for dual radioactive and fluorescent labeling of sEVs. This methodology enables in vivo and in vitro study of these vesicles after exogenous administration. The dual nanoprobe would be a promising technology for cancer diagnosis and a powerful tool for studying the biological behavior of these nanosystems for use in drug delivery.Publication Extracellular Vesicles in Cancer: Cell-to-Cell Mediators of Metastasis.(Cell Press, 2016-12-12) Becker, Annette; Thakur, Basant Kumar; Weiss, Joshua Mitchell; Kim, Han Sang; Peinado, Hector; Lyden, DavidTumor-secreted extracellular vesicles (EVs) are critical mediators of intercellular communication between tumor cells and stromal cells in local and distant microenvironments. Accordingly, EVs play an essential role in both primary tumor growth and metastatic evolution. EVs orchestrate multiple systemic pathophysiological processes, such as coagulation, vascular leakiness, and reprogramming of stromal recipient cells to support pre-metastatic niche formation and subsequent metastasis. Clinically, EVs may be biomarkers and novel therapeutic targets for cancer progression, particularly for predicting and preventing future metastatic development.Publication Gut Microbiota and Therapy in Metastatic Melanoma: Focus on MAPK Pathway Inhibition.(2022-10-09) Guardamagna, Mora; Berciano-Guerrero, Miguel-Angel; Villaescusa-González, Beatriz; Perez-Ruiz, Elisabeth; Oliver, Javier; Lavado-Valenzuela, Rocío; Rueda-Dominguez, Antonio; Barragán, Isabel; Queipo-Ortuño, María IsabelGut microbiome (GM) and its either pro-tumorigenic or anti-tumorigenic role is intriguing and constitutes an evolving landscape in translational oncology. It has been suggested that these microorganisms may be involved in carcinogenesis, cancer treatment response and resistance, as well as predisposition to adverse effects. In melanoma patients, one of the most immunogenic cancers, immune checkpoint inhibitors (ICI) and MAPK-targeted therapy-BRAF/MEK inhibitors-have revolutionized prognosis, and the study of the microbiome as a modulating factor is thus appealing. Although BRAF/MEK inhibitors constitute one of the main backbones of treatment in melanoma, little is known about their impact on GM and how this might correlate with immune re-induction. On the contrary, ICI and their relationship to GM has become an interesting field of research due to the already-known impact of immunotherapy in modulating the immune system. Immune reprogramming in the tumor microenvironment has been established as one of the main targets of microbiome, since it can induce immunosuppressive phenotypes, promote inflammatory responses or conduct anti-tumor responses. As a result, ongoing clinical trials are evaluating the role of fecal microbiota transplant (FMT), as well as the impact of using dietary supplements, antibiotics and probiotics in the prediction of response to therapy. In this review, we provide an overview of GM's link to cancer, its relationship with the immune system and how this may impact response to treatments in melanoma patients. We also discuss insights about novel therapeutic approaches including FMT, changes in diet and use of probiotics, prebiotics and symbiotics. Finally, we hypothesize on the possible pathways through which GM may impact anti-tumor efficacy in melanoma patients treated with targeted therapy, an appealing subject of which little is known.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 Immunotherapy in NSCLC patients with brain metastases. Understanding brain tumor microenvironment and dissecting outcomes from immune checkpoint blockade in the clinic [Pre-print](Elsevier, 2020-09) Vilariño, N; Bruna, J; Nadal, E; Bosch-Barrera, J; Valiente, M; Vilariño, N.; Bruna, J.; Bosch-Barrera, J.; Valiente, M.; Nadal, E.; Government of Catalonia (España); Ministerio de Ciencia, Innovación y Universidades (España)Brain metastases are frequent complications in patients with non-small-cell lung cancer (NSCLC) associated with significant morbidity and poor prognosis. Our goal is to give a global overlook on clinical efficacy from immune checkpoint inhibitors in this setting and to review the role of biomarkers and molecular interactions in brain metastases from patients with NSCLC. We reviewed clinical trials reporting clinical outcomes of patients with NSCLC with brain metastases as well as publications assessing the tumor microenvironment and the complex molecular interactions of tumor cells with immune and resident cells in brain metastases from NSCLC biopsies or preclinical models. Although limited data are available on immunotherapy in patients with brain metastases, immune checkpoint inhibitors alone or in combination with chemotherapy have shown promising intracranial efficacy and safety results. The underlying mechanism of action of immune checkpoint inhibitors in the brain niche and their influence on tumor microenvironment are still not known. Lower PD-L1 expression and less T CD8+ infiltration were found in brain metastases compared with matched NSCLC primary tumors, suggesting an immunosuppressive microenvironment in the brain. Reactive astrocytes and tumor associated macrophages are paramount in NSCLC brain metastases and play a role in promoting tumor progression and immune evasion. Discordances in the immune profile between primary tumours and brain metastases underscore differences in the tumour microenvironment and immune system interactions within the lung and brain niche. The characterization of immune phenotype of brain metastases and dissecting the interplay among immune cells and resident stromal cells along with cancer cells is crucial to unravel effective immunotherapeutic approaches in patients with NSCLC and brain metastases.Publication Intratumoral Immunotherapy with XCL1 and sFlt3L Encoded in Recombinant Semliki Forest Virus-Derived Vectors Fosters Dendritic Cell-Mediated T-cell Cross-Priming(American Association for Cancer Research (AACR), 2018-12) Sánchez-Paulete, Alfonso R; Teijeira, Álvaro; Quetglas, José I; Rodríguez-Ruiz, María E; Sánchez-Arráez, Álvaro; Labiano, Sara; Etxeberria, Iñaki; Azpilikueta, Arantza; Bolaños, Elixabet; Ballesteros-Briones, María Cristina; Casares, Noelia; Quezada, Sergio A; Berraondo, Pedro; Sancho, David; Smerdou, Cristian; Melero, Ignacio; Ministerio de Economía y Competitividad (España); Cancer Resarch Institute (Estados Unidos); Unión Europea. Comisión Europea; Instituto de Salud Carlos III: Multiple lines of evidence indicate a critical role of antigen cross-presentation by conventional BATF3-dependent type 1 classical dendritic cells (cDC1) in CD8-mediated antitumor immunity. Flt3L and XCL1, respectively, constitute a key growth/differentiation factor and a potent and specific chemoattractant for cDC1. To exploit their antitumor functions in local immunotherapy, we prepared Semliki Forest Virus (SFV)-based vectors encoding XCL1 and soluble Flt3L (sFlt3L). These vectors readily conferred transgene expression to the tumor cells in culture and when engrafted as subcutaneous mouse tumor models. In syngeneic mice, intratumoral injection of SFV-XCL1-sFlt3L (SFV-XF) delayed progression of MC38- and B16-derived tumors. Therapeutic activity was observed and exerted additive effects in combination with anti-PD-1, anti-CD137, or CTLA-4 immunostimulatory mAbs. Therapeutic effects were abolished by CD8β T-cell depletion and were enhanced by CD4 T-cell depletion, but not by T regulatory cell predepletion with anti-CD25 mAb. Antitumor effects were also abolished in BATF3- and IFNAR-deficient mice. In B16-OVA tumors, SFV-XF increased the number of infiltrating CD8 T cells, including those recognizing OVA. Consistently, following the intratumoral SFV-XF treatment courses, we observed increased BATF3-dependent cDC1 among B16-OVA tumor-infiltrating leukocytes. Such an intratumoral increase was not seen in MC38-derived tumors, but both resident and migratory cDC1 were boosted in SFV-XF-treated MC38 tumor-draining lymph nodes. In conclusion, viral gene transfer of sFlt3L and XCL1 is feasible, safe, and biologically active in mice, exerting antitumor effects that can be potentiated by CD4 T-cell depletion. SIGNIFICANCE: These findings demonstrate that transgenic expression of sFLT3L and XCL1 in tumor cells mediates cross-priming of, and elicits potent antitumor activity from, CD8 T lymphocytes, particularly in combination with CD4 T-cell depletion.Publication Leukemic cell-secreted interleukin-9 suppresses cytotoxic T cell-mediated killing in chronic lymphocytic leukemia.(Springer, 2024-02-15) Boncompagni, Gioia; Tatangelo, Vanessa; Lopresti, Ludovica; Ulivieri, Cristina; Capitani, Nagaja; Tangredi, Carmela; Finetti, Francesca; Marotta, Giuseppe; Frezzato, Federica; Visentin, Andrea; Ciofini, Sara; Gozzetti, Alessandro; Bocchia, Monica; Calzada-Fraile, Diego; Martin Cofreces, Noa B; Trentin, Livio; Patrussi, Laura; Baldari, Cosima T; Unión Europea. Comisión Europea. H2020The tumor microenvironment (TME) plays a central role in the pathogenesis of chronic lymphocytic leukemia (CLL), contributing to disease progression and chemoresistance. Leukemic cells shape the TME into a pro-survival and immunosuppressive niche through contact-dependent and contact-independent interactions with the cellular components of the TME. Immune synapse (IS) formation is defective in CLL. Here we asked whether soluble factors released by CLL cells contribute to their protection from cytotoxic T cell (CTL)-mediated killing by interfering with this process. We found that healthy CTLs cultured in media conditioned by leukemic cells from CLL patients or Eμ-TCL1 mice upregulate the exhaustion marker PD-1 and become unable to form functional ISs and kill target cells. These defects were more pronounced when media were conditioned by leukemic cells lacking p66Shc, a proapoptotic adapter whose deficiency has been implicated in disease aggressiveness both in CLL and in the Eμ-TCL1 mouse model. Multiplex ELISA assays showed that leukemic cells from Eμ-TCL1 mice secrete abnormally elevated amounts of CCL22, CCL24, IL-9 and IL-10, which are further upregulated in the absence of p66Shc. Among these, IL-9 and IL-10 were also overexpressed in leukemic cells from CLL patients, where they inversely correlated with residual p66Shc. Using neutralizing antibodies or the recombinant cytokines we show that IL-9, but not IL-10, mediates both the enhancement in PD-1 expression and the suppression of effector functions in healthy CTLs. Our results demonstrate that IL-9 secreted by leukemic cells negatively modulates the anti-tumor immune abilities of CTLs, highlighting a new suppressive mechanism and a novel potential therapeutical target in CLL.Publication LIF regulates CXCL9 in tumor-associated macrophages and prevents CD8+ T cell tumor-infiltration impairing anti-PD1 therapy(Nature Publishing Group, 2019-06-11) Pascual-García, Mónica; Bonfill-Teixidor, Ester; Planas-Rigol, Ester; Rubio-Perez, Carlota; Iurlaro, Raffaella; Arias, Alexandra; Cuartas, Isabel; Sala-Hojman, Ada; Escudero, Laura; Martínez-Ricarte, Francisco; Huber-Ruano, Isabel; Nuciforo, Paolo; Pedrosa, Leire; Marques, Carolina; Braña, Irene; Garralda, Elena; Vieito, María; Squatrito, Massimo; Pineda, Estela; Graus, Francesc; Espejo, Carmen; Sahuquillo, Juan; Tabernero, Josep; Seoane, Joan; Unión Europea. Comisión Europea. European Research Council (ERC); Asociación Española Contra el Cáncer; Instituto de Salud Carlos III; FERO Foundation; Fundación La Caixa; Fundación BBVA; Cellex FoundationCancer response to immunotherapy depends on the infiltration of CD8+ T cells and the presence of tumor-associated macrophages within tumors. Still, little is known about the determinants of these factors. We show that LIF assumes a crucial role in the regulation of CD8+ T cell tumor infiltration, while promoting the presence of protumoral tumor-associated macrophages. We observe that the blockade of LIF in tumors expressing high levels of LIF decreases CD206, CD163 and CCL2 and induces CXCL9 expression in tumor-associated macrophages. The blockade of LIF releases the epigenetic silencing of CXCL9 triggering CD8+ T cell tumor infiltration. The combination of LIF neutralizing antibodies with the inhibition of the PD1 immune checkpoint promotes tumor regression, immunological memory and an increase in overall survival.Publication Macrophages, inflammation, and tumor suppressors: ARF, a new player in the game(Hindawi, 2012) Través, Paqui G; Luque, Alfonso; Hortelano, Sonsoles; Instituto de Salud Carlos IIIThe interaction between tumor progression and innate immune system has been well established in the last years. Indeed, several lines of clinical evidence indicate that immune cells such as tumor-associated macrophages (TAMs) interact with tumor cells, favoring growth, angiogenesis, and metastasis of a variety of cancers. In most tumors, TAMs show properties of an alternative polarization phenotype (M2) characterized by the expression of a series of chemokines, cytokines, and proteases that promote immunosuppression, tumor proliferation, and spreading of the cancer cells. Tumor suppressor genes have been traditionally linked to the regulation of cancer progression; however, a growing body of evidence indicates that these genes also play essential roles in the regulation of innate immunity pathways through molecular mechanisms that are still poorly understood. In this paper, we provide an overview of the immunobiology of TAMs as well as what is known about tumor suppressors in the context of immune responses. Recent advances regarding the role of the tumor suppressor ARF as a regulator of inflammation and macrophage polarization are also reviewed.Publication Metabolic Reprogramming in Tumor Endothelial Cells.(2022-09-21) García-Caballero, Melissa; Sokol, Liliana; Cuypers, Anne; Carmeliet, PeterThe dynamic crosstalk between the different components of the tumor microenvironment is critical to determine cancer progression, metastatic dissemination, tumor immunity, and therapeutic responses. Angiogenesis is critical for tumor growth, and abnormal blood vessels contribute to hypoxia and acidosis in the tumor microenvironment. In this hostile environment, cancer and stromal cells have the ability to alter their metabolism in order to support the high energetic demands and favor rapid tumor proliferation. Recent advances have shown that tumor endothelial cell metabolism is reprogrammed, and that targeting endothelial metabolic pathways impacts developmental and pathological vessel sprouting. Therefore, the use of metabolic antiangiogenic therapies to normalize the blood vasculature, in combination with immunotherapies, offers a clinical niche to treat cancer.Publication Metabolism of tissue macrophages in homeostasis and pathology.(Springer, 2022-03) Wculek, Stefanie K; Dunphy, Gillian; Heras-Murillo, Ignacio; Mastrangelo, Annalaura; Sancho, David; Fundación La Caixa; European Molecular Biology Organization; Unión Europea. Comisión Europea; Unión Europea. Comisión Europea. European Research Council (ERC); Agencia Estatal de Investigación (España); Comunidad de Madrid (España); Atresmedia; Fundación Banco Santander; Fundación La Marató TV3; Instituto de Salud Carlos III; Ministerio de Ciencia e Innovación (España); Fundación ProCNICCellular metabolism orchestrates the intricate use of tissue fuels for catabolism and anabolism to generate cellular energy and structural components. The emerging field of immunometabolism highlights the importance of cellular metabolism for the maintenance and activities of immune cells. Macrophages are embryo- or adult bone marrow-derived leukocytes that are key for healthy tissue homeostasis but can also contribute to pathologies such as metabolic syndrome, atherosclerosis, fibrosis or cancer. Macrophage metabolism has largely been studied in vitro. However, different organs contain diverse macrophage populations that specialize in distinct and often tissue-specific functions. This context specificity creates diverging metabolic challenges for tissue macrophage populations to fulfill their homeostatic roles in their particular microenvironment and conditions their response in pathological conditions. Here, we outline current knowledge on the metabolic requirements and adaptations of macrophages located in tissues during homeostasis and selected diseases.Publication Midkine rewires the melanoma microenvironment toward a tolerogenic and immune-resistant state.(Nature Publishing Group, 2020-12) Cerezo-Wallis, Daniela; Contreras-Alcalde, Marta; Troulé, Kevin; Catena, Xavier; Mucientes, Cynthia; Calvo, Tonantzin G; Cañón, Estela; Tejedo, Cristina; Pennacchi, Paula C; Hogan, Sabrina; Kölblinger, Peter; Tejero, Héctor; Chen, Andrew X; Ibarz, Nuria; Graña-Castro, Osvaldo; Martinez Garcia, Maria Dolores; Muñoz, Javier; Ortiz-Romero, Pablo; Rodriguez-Peralto, José L; Gómez-López, Gonzalo; Al-Shahrour, Fatima; Rabadán, Raúl; Levesque, Mitchell P; Olmeda, David; Soengas, MS; Melanoma Research Alliance; Worldwide Cancer Research; Asociación Española Contra el Cáncer; Instituto de Salud Carlos III; Ministerio de Ciencia y Competitividad (España); Fundación La Caixa; Marie Curie; Unión Europea. Comisión Europea. H2020An open question in aggressive cancers such as melanoma is how malignant cells can shift the immune system to pro-tumorigenic functions. Here we identify midkine (MDK) as a melanoma-secreted driver of an inflamed, but immune evasive, microenvironment that defines poor patient prognosis and resistance to immune checkpoint blockade. Mechanistically, MDK was found to control the transcriptome of melanoma cells, allowing for coordinated activation of nuclear factor-κB and downregulation of interferon-associated pathways. The resulting MDK-modulated secretome educated macrophages towards tolerant phenotypes that promoted CD8+ T cell dysfunction. In contrast, genetic targeting of MDK sensitized melanoma cells to anti-PD-1/anti-PD-L1 treatment. Emphasizing the translational relevance of these findings, the expression profile of MDK-depleted tumors was enriched in key indicators of a good response to immune checkpoint blockers in independent patient cohorts. Together, these data reveal that MDK acts as an internal modulator of autocrine and paracrine signals that maintain immune suppression in aggressive melanomas.Publication Mitochondrial Morphological and Functional Reprogramming Following CD137 (4-1BB) Costimulation.(American Association for Cancer Research (AACR), 2018-07) Teijeira, Alvaro; Labiano, Sara; Garasa, Saray; Etxeberria, Iñaki; Santamaría, Eva; Rouzaut, Ana; Enamorado, Michel; Azpilikueta, Arantza; Inoges, Susana; Bolaños, Elixabet; Aznar, Maria Angela; Sánchez-Paulete, Alfonso R; Sancho, David; Melero, Ignacio; imCORE Network; Ministerio de Ciencia y Competitividad (España); Unión Europea. Comisión Europea. 7 Programa Marco; Unión Europea. Comisión Europea. H2020; Fundación BBVAT and NK lymphocytes express CD137 (4-1BB), a costimulatory receptor of the TNFR family whose function is exploitable for cancer immunotherapy. Mitochondria regulate the function and survival of T lymphocytes. Herein, we show that CD137 costimulation provided by agonist mAb and CD137L (4-1BBL) induced mitochondria enlargement that resulted in enhanced mitochondrial mass and transmembrane potential in human and mouse CD8+ T cells. Such mitochondrial changes increased T-cell respiratory capacities and were critically dependent on mitochondrial fusion protein OPA-1 expression. Mass and function of mitochondria in tumor-reactive CD8+ T cells from cancer-bearing mice were invigorated by agonist mAb to CD137, whereas mitochondrial baseline mass and function were depressed in CD137-deficient tumor reactive T cells. Tumor rejection induced by the synergistic combination of adoptive T-cell therapy and agonistic anti-CD137 was critically dependent on OPA-1 expression in transferred CD8+ T cells. Moreover, stimulation of CD137 with CD137 mAb in short-term cultures of human tumor-infiltrating lymphocytes led to mitochondria enlargement and increased transmembrane potential. Collectively, these data point to a critical link between mitochondrial morphology and function and enhanced antitumor effector activity upon CD137 costimulation of T cells. Cancer Immunol Res; 6(7); 798-811. ©2018 AACR.Publication PD-L1ATTAC mice reveal the potential of depleting PD-L1 expressing cells in cancer therapy.(Impact Journals, 2023-03-22) Fueyo-Marcos, Elena; Lopez-Pernas, Gema; Fustero-Torre, Coral; Antón, Marta Elena; Al-Shahrour, Fátima; Fernández-Capetillo, Oscar; Murga, Matilde; Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Asociación Española Contra el Cáncer; Instituto de Salud Carlos III; Ministerio de Ciencia, Innovación y Universidades (España)Antibodies targeting the PD-1 receptor and its ligand PD-L1 have shown impressive responses in some tumors of bad prognosis. We hypothesized that, since immunosuppressive cells might present several immune checkpoints on their surface, the selective elimination of PD-L1 expressing cells could be efficacious in enabling the activation of antitumoral immune responses. To address this question, we developed an inducible suicidal knock-in mouse allele of Pd-l1 (PD-L1ATTAC) which allows for the tracking and specific elimination of PD-L1-expressing cells in adult tissues. Consistent with our hypothesis, elimination of PD-L1 expressing cells from the mouse peritoneum increased the septic response to lipopolysaccharide (LPS), due to an exacerbated inflammatory response to the endotoxin. In addition, mice depleted of PD-L1+ cells were resistant to colon cancer peritoneal allografts, which was associated with a loss of immunosuppressive B cells and macrophages, concomitant with an increase in activated cytotoxic CD8 T cells. Collectively, these results illustrate the usefulness of PD-L1ATTAC mice for research in immunotherapy and provide genetic support to the concept of targeting PD-L1 expressing cells in cancer.Publication Pre-metastatic niches: organ-specific homes for metastases(2017-05) Peinado, Héctor; Zhang, Haiying; Matei, Irina R; Costa-Silva, Bruno; Hoshino, Ayuko; Rodrigues, Goncalo; Psaila, Bethan; Kaplan, Rosandra N; Bromberg, Jacqueline F; Kang, Yibin; Bissell, Mina J; Cox, Thomas R; Giaccia, Amato J; Erler, Janine T; Hiratsuka, Sachie; Ghajar, Cyrus M; Lyden, DavidIt is well established that organs of future metastasis are not passive receivers of circulating tumour cells, but are instead selectively and actively modified by the primary tumour before metastatic spread has even occurred. Sowing the 'seeds' of metastasis requires the action of tumour-secreted factors and tumour-shed extracellular vesicles that enable the 'soil' at distant metastatic sites to encourage the outgrowth of incoming cancer cells. In this Review, we summarize the main processes and new mechanisms involved in the formation of the pre-metastatic niche.