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dc.contributor.authorCarmona Rodríguez, Lorenaes_ES
dc.contributor.authorMartínez Rey, Diegoes_ES
dc.contributor.authorFernández Aceñero, María Jesúses_ES
dc.contributor.authorGonzález Martín, Aliciaes_ES
dc.contributor.authorPaz Cabezas, Mateoes_ES
dc.contributor.authorRodríguez Rodríguez, Noees_ES
dc.contributor.authorPérez Villamil, Beatrizes_ES
dc.contributor.authorSáez, María Eugeniaes_ES
dc.contributor.authorDíaz Rubio, Eduardoes_ES
dc.contributor.authorMira, Emiliaes_ES
dc.contributor.authorMañes, Santoses_ES
dc.identifier.citationJournal for immunotherapy of cancer 8 (1): e000432. (2020)es_ES
dc.description.abstractBackground Tumor-infiltrating lymphocytes (TILs), mainly CD8+ cytotoxic T lymphocytes (CTL), are linked to immune-mediated control of human cancers and response to immunotherapy. Tumors have nonetheless developed specific mechanisms that selectively restrict T cell entry into the tumor microenvironment. The extracellular superoxide dismutase (SOD3) is an anti-oxidant enzyme usually downregulated in tumors. We hypothesize that upregulation of SOD3 in the tumor microenvironment might be a mechanism to boost T cell infiltration by normalizing the tumor-associated endothelium. Results Here we show that SOD3 overexpression in endothelial cells increased in vitro transmigration of naïve and activated CD4+ and CD8+ T cells, but not of myeloid cells. Perivascular expression of SOD3 also specifically increased CD4+ and CD8+ effector T cell infiltration into tumors and improved the effectiveness of adoptively transferred tumor-specific CD8+ T cells. SOD3-induced enhanced transmigration in vitro and tumor infiltration in vivo were not associated to upregulation of T cell chemokines such as CXCL9 or CXCL10, nor to changes in the levels of endothelial adhesion receptors such as intercellular adhesion molecule-1 (ICAM-1) or vascular cell adhesion molecule-1 (VCAM-1). Instead, SOD3 enhanced T cell infiltration via HIF-2α-dependent induction of specific WNT ligands in endothelial cells; this led to WNT signaling pathway activation in the endothelium, FOXM1 stabilization, and transcriptional induction of laminin-α4 (LAMA4), an endothelial basement membrane component permissive for T cell infiltration. In patients with stage II colorectal cancer, SOD3 was associated with increased CD8+ TIL density and disease-free survival. SOD3 expression was also linked to a T cell–inflamed gene signature using the COAD cohort from The Cancer Genome Atlas program. Conclusion Our findings suggest that SOD3-induced upregulation of LAMA4 in endothelial cells boosts selective tumor infiltration by T lymphocytes, thus transforming immunologically “cold” into “hot” tumors. High SOD3 levels are associated with human colon cancer infiltration by CD8+ T cells, with potential consequences for the clinical outcome of these patients. Our results also uncover a cell type–specific, distinct activity of the WNT pathway for the regulation of T cell infiltration into tumors.es_ES
dc.description.sponsorshipThis work was funded by grants from the Spanish Ministerio de Economía y Competitividad (MINECO) and the Comunidad de Madrid.es_ES
dc.publisherBMJ Publishing Groupes_ES
dc.relation.isversionofPublisher's versiones_ES
dc.titleSOD3 induces a HIF-2α-dependent program in endothelial cells that provides a selective signal for tumor infiltration by T cellses_ES
dc.description.peerreviewedPeer reviewedes_ES
dc.contributor.funderMinisterio de Economía y Competitividad (España)es_ES
dc.contributor.funderComunidad de Madrides_ES
oprm.item.hasRevisionno ko 0 false*
dc.contributor.orcidMañes, Santos [0000-0001-8023-957X]es_ES
dc.contributor.orcidMira, Emilia [0000-0002-4226-1829]es_ES
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