000168695 001__ 168695 000168695 005__ 20260217214838.0 000168695 0247_ $$2doi$$a10.1038/s41418-018-0112-9 000168695 0248_ $$2sideral$$a106459 000168695 037__ $$aART-2018-106459 000168695 041__ $$aeng 000168695 100__ $$0(orcid)0000-0002-8731-4269$$aJaime-Sánchez, P. 000168695 245__ $$aAntigen-specific primed cytotoxic T cells eliminate tumour cells in vivo and prevent tumour development, regardless of the presence of anti-apoptotic mutations conferring drug resistance 000168695 260__ $$c2018 000168695 5203_ $$aCytotoxic CD8+ T (Tc) cells are the main executors of transformed and cancer cells during cancer immunotherapy. The latest clinical results evidence a high efficacy of novel immunotherapy agents that modulate Tc cell activity against bad prognosis cancers. However, it has not been determined yet whether the efficacy of these treatments can be affected by selection of tumoural cells with mutations in the cell death machinery, known to promote drug resistance and cancer recurrence. Here, using a model of prophylactic tumour vaccination based on the LCMV-gp33 antigen and the mouse EL4 T lymphoma, we analysed the molecular mechanism employed by Tc cells to eliminate cancer cells in vivo and the impact of mutations in the apoptotic machinery on tumour development. First of all, we found that Tc cells, and perf and gzmB are required to efficiently eliminate EL4.gp33 cells after LCMV immunisation during short-term assays (1–4 h), and to prevent tumour development in the long term. Furthermore, we show that antigen-pulsed chemoresistant EL4 cells overexpressing Bcl-XL or a dominant negative form of caspase-3 are specifically eliminated from the peritoneum of infected animals, as fast as parental EL4 cells. Notably, antigen-specific Tc cells control the tumour growth of the mutated cells, as efficiently as in the case of parental cells. Altogether, expression of the anti-apoptotic mutations does not confer any advantage for tumour cells neither in the short-term survival nor in long-term tumour formation. Although the mechanism involved in the elimination of the apoptosis-resistant tumour cells is not completely elucidated, neither necroptosis nor pyroptosis seem to be involved. Our results provide the first experimental proof that chemoresistant cancer cells with mutations in the main cell death pathways are efficiently eliminated by Ag-specific Tc cells in vivo during immunotherapy and, thus, provide the molecular basis to treat chemoresistant cancer cells with CD8 Tc-based immunotherapy. 000168695 536__ $$9info:eu-repo/grantAgreement/ES/MINECO-FEDER/SAF2011-25390$$9info:eu-repo/grantAgreement/ES/MINECO/SAF2014-54763-C2-1$$9info:eu-repo/grantAgreement/ES/MINECO/SAF2017-83120-C2-1-R 000168695 540__ $$9info:eu-repo/semantics/closedAccess$$aAll rights reserved$$uhttp://www.europeana.eu/rights/rr-f/ 000168695 590__ $$a8.086$$b2018 000168695 591__ $$aCELL BIOLOGY$$b28 / 191 = 0.147$$c2018$$dQ1$$eT1 000168695 591__ $$aBIOCHEMISTRY & MOLECULAR BIOLOGY$$b27 / 294 = 0.092$$c2018$$dQ1$$eT1 000168695 592__ $$a3.98$$b2018 000168695 593__ $$aMolecular Biology$$c2018$$dQ1 000168695 593__ $$aCell Biology$$c2018$$dQ1 000168695 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion 000168695 700__ $$aCatalán, E. 000168695 700__ $$aUranga-Murillo, I. 000168695 700__ $$0(orcid)0000-0001-7897-9173$$aAguiló, N.$$uUniversidad de Zaragoza 000168695 700__ $$0(orcid)0000-0002-1861-5981$$aSantiago, L.$$uUniversidad de Zaragoza 000168695 700__ $$0(orcid)0000-0001-7328-2094$$aLanuza, P.M.$$uUniversidad de Zaragoza 000168695 700__ $$0(orcid)0000-0002-8486-8514$$ade Miguel, D. 000168695 700__ $$0(orcid)0000-0002-9730-2210$$aArias, M.A.$$uUniversidad de Zaragoza 000168695 700__ $$0(orcid)0000-0003-0154-0730$$aPardo, J.$$uUniversidad de Zaragoza 000168695 7102_ $$11008$$2630$$aUniversidad de Zaragoza$$bDpto. Microb.Med.Pr.,Sal.Públ.$$cÁrea Microbiología 000168695 7102_ $$11008$$2566$$aUniversidad de Zaragoza$$bDpto. Microb.Med.Pr.,Sal.Públ.$$cÁrea Inmunología 000168695 7102_ $$11002$$2060$$aUniversidad de Zaragoza$$bDpto. Bioq.Biolog.Mol. Celular$$cÁrea Bioquímica y Biolog.Mole. 000168695 773__ $$g25 (2018), 1536 – 1548$$pCell death differ.$$tCell Death and Differentiation$$x1350-9047 000168695 8564_ $$s2855609$$uhttps://zaguan.unizar.es/record/168695/files/texto_completo.pdf$$yVersión publicada 000168695 8564_ $$s2359482$$uhttps://zaguan.unizar.es/record/168695/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada 000168695 909CO $$ooai:zaguan.unizar.es:168695$$particulos$$pdriver 000168695 951__ $$a2026-02-17-20:13:32 000168695 980__ $$aARTICLE