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dc.contributor.authorJaime-Sanchez, Paula
dc.contributor.authorUranga-Murillo, Iratxe
dc.contributor.authorAguilo, Nacho
dc.contributor.authorKhouili, Sofia C. 
dc.contributor.authorArias, Maykel A
dc.contributor.authorSancho, David 
dc.contributor.authorPardo, Julian
dc.identifier.citationJ Immunother Cancer. 2020; 8(1):e000528es_ES
dc.description.abstractBACKGROUND: Elimination of cancer cells by some stimuli like chemotherapy and radiotherapy activates anticancer immunity after the generation of damage-associated molecular patterns, a process recently named immunogenic cell death (ICD). Despite the recent advances in cancer immunotherapy, very little is known about the immunological consequences of cell death activated by cytotoxic CD8+ T (Tc) cells on cancer cells, that is, if Tc cells induce ICD on cancer cells and the molecular mechanisms involved. METHODS: ICD induced by Tc cells on EL4 cells was analyzed in tumor by vaccinating mice with EL4 cells killed in vitro or in vivo by Ag-specific Tc cells. EL4 cells and mutants thereof overexpressing Bcl-XL or a dominant negative mutant of caspase-3 and wild-type mice, as well as mice depleted of Tc cells and mice deficient in perforin, TLR4 and BATF3 were used. Ex vivo cytotoxicity of spleen cells from immunized mice was analyzed by flow cytometry. Expression of ICD signals (calreticulin, HMGB1 and interleukin (IL)-1β) was analyzed by flow cytometry and ELISA. RESULTS: Mice immunized with EL4.gp33 cells killed in vitro or in vivo by gp33-specific Tc cells were protected from parental EL4 tumor development. This result was confirmed in vivo by using ovalbumin (OVA) as another surrogate antigen. Perforin and TLR4 and BATF3-dependent type 1 conventional dendritic cells (cDC1s) were required for protection against tumor development, indicating cross-priming of Tc cells against endogenous EL4 tumor antigens. Tc cells induced ICD signals in EL4 cells. Notably, ICD of EL4 cells was dependent on caspase-3 activity, with reduced antitumor immunity generated by caspase-3-deficient EL4 cells. In contrast, overexpression of Bcl-XL in EL4 cells had no effect on induction of Tc cell antitumor response and protection. CONCLUSIONS: Elimination of tumor cells by Ag-specific Tc cells is immunogenic and protects against tumor development by generating new Tc cells against EL4 endogenous antigens. This finding helps to explain the enhanced efficacy of T cell-dependent immunotherapy and provide a molecular basis to explain the epitope spread phenomenon observed during vaccination and chimeric antigen receptor (CAR)-T cell therapy. In addition, they suggest that caspase-3 activity in the tumor may be used as a biomarker to predict cancer recurrence during T cell-dependent immunotherapies.es_ES
dc.description.sponsorshipWork in the JP laboratory is funded by Asociacion de Padres de Niños con Cancer de Aragon (ASPANOA), FEDER (Fondo Europeo de Desarrollo Regional, Gobierno de Aragón(Group B29_17R) and Ministerio de Ciencia, Innovación e Universidades (MCNU), Agencia Estatal de Investigación (SAF2014-54763-C2-1 and SAF2017‐83120‐C2‐1‐R). Predoctoral grants/contracts from Fundación Santander/Universidad de Zaragoza (MA), and Gobierno de Aragon (IUM, PJS) and a postdoctoral Juan de la Cierva Contract (MA). JP is supported by ARAID Foundation. Work in the DS laboratory is funded by the CNIC, from Ministerio de Ciencia, Innovación e Universidades (MCNU), Agencia Estatal de Investigación and Fondo Europeo de Desarrollo Regional (FEDER) (SAF2016-79040-R) and the European Research Council (ERC-2016-Consolidator Grant 725091). The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the MCNU and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505).es_ES
dc.publisherBMJ Journalses_ES
dc.relation.isversionofPublisher's versiones_ES
dc.subjectdendritic cellses_ES
dc.titleCell death induced by cytotoxic CD8+ T cells is immunogenic and primes caspase-3-dependent spread immunity against endogenous tumor antigenses_ES
dc.rights.licenseAtribución-NoComercial 4.0 Internacional*
dc.contributor.funderAsociación de Padres de Niños con Cancer de Aragónes_ES
dc.contributor.funderGobierno de Aragónes_ES
dc.contributor.funderEuropean Regional Development Fund (ERDF/FEDER)es_ES
dc.contributor.funderMinisterio de Ciencia, Innovación y Universidades (MCNU)es_ES
dc.contributor.funderARAID Foundationes_ES
dc.contributor.funderInstituto de Salud Carlos III - ISCIIIes_ES
dc.contributor.funderFundación ProCNICes_ES
dc.contributor.funderEuropean Research Counciles_ES
dc.identifier.journalJournal for immunotherapy of canceres_ES
dc.repisalud.orgCNICCNIC::Grupos de investigación::Inmunobiologíaes_ES

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