000089710 001__ 89710
000089710 005__ 20210902121706.0
000089710 0247_ $$2doi$$a10.1136/jitc-2020-000528
000089710 0248_ $$2sideral$$a117847
000089710 037__ $$aART-2020-117847
000089710 041__ $$aeng
000089710 100__ $$0(orcid)0000-0002-8731-4269$$aJaime-Sanchez, Paula
000089710 245__ $$aCell death induced by cytotoxic CD8 + T cells is immunogenic and primes caspase-3-dependent spread immunity against endogenous tumor antigens
000089710 260__ $$c2020
000089710 5060_ $$aAccess copy available to the general public$$fUnrestricted
000089710 5203_ $$aBackground 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-X L 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)-1ß) 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-X L 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.
000089710 536__ $$9info:eu-repo/grantAgreement/ES/MINECO/SAF2014-54763-C2-1-R$$9info:eu-repo/grantAgreement/ES/MICINN/SAF2016-79040-R$$9This project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No H2020 725091-MITOMAD$$9info:eu-repo/grantAgreement/EC/H2020/725091/EU/Functional characterisation of mitochondrial metabolic adaptations to innate sensing in dendritic cell subsets/MITOMAD$$9info:eu-repo/grantAgreement/ES/DGA/B29$$9info:eu-repo/grantAgreement/ES/MINECO/SAF2017-83120-C2-1-R$$9info:eu-repo/grantAgreement/ES/MINECO/SEV-2015-0505
000089710 540__ $$9info:eu-repo/semantics/openAccess$$aby-nc$$uhttp://creativecommons.org/licenses/by-nc/3.0/es/
000089710 590__ $$a13.751$$b2020
000089710 591__ $$aONCOLOGY$$b15 / 242 = 0.062$$c2020$$dQ1$$eT1
000089710 591__ $$aIMMUNOLOGY$$b8 / 162 = 0.049$$c2020$$dQ1$$eT1
000089710 592__ $$a5.059$$b2020
000089710 593__ $$aCancer Research$$c2020$$dQ1
000089710 593__ $$aImmunology$$c2020$$dQ1
000089710 593__ $$aPharmacology$$c2020$$dQ1
000089710 593__ $$aMolecular Medicine$$c2020$$dQ1
000089710 593__ $$aOncology$$c2020$$dQ1
000089710 593__ $$aImmunology and Allergy$$c2020$$dQ1
000089710 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion
000089710 700__ $$aUranga-Murillo, Iratxe
000089710 700__ $$0(orcid)0000-0001-7897-9173$$aAguilo, Nacho$$uUniversidad de Zaragoza
000089710 700__ $$aKhouili, Sofía C.
000089710 700__ $$aArias, Maykel A.
000089710 700__ $$aSancho, David
000089710 700__ $$0(orcid)0000-0003-0154-0730$$aPardo, Julián$$uUniversidad de Zaragoza
000089710 7102_ $$11011$$2630$$aUniversidad de Zaragoza$$bDpto. Microb.Ped.Radio.Sal.Pú.$$cÁrea Microbiología
000089710 7102_ $$11011$$2566$$aUniversidad de Zaragoza$$bDpto. Microb.Ped.Radio.Sal.Pú.$$cÁrea Inmunología
000089710 773__ $$g8, 1 (2020), 000528 1-14$$pJ. immunotherap. cancer$$tJournal for ImmunoTherapy of Cancer$$x2051-1426
000089710 8564_ $$s3031858$$uhttps://zaguan.unizar.es/record/89710/files/texto_completo.pdf$$yVersión publicada
000089710 8564_ $$s122412$$uhttps://zaguan.unizar.es/record/89710/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada
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000089710 951__ $$a2021-09-02-09:17:36
000089710 980__ $$aARTICLE