000048608 001__ 48608 000048608 005__ 20210121114531.0 000048608 0247_ $$2doi$$a10.1158/1078-0432.CCR-15-0685 000048608 0248_ $$2sideral$$a94405 000048608 037__ $$aART-2015-94405 000048608 041__ $$aeng 000048608 100__ $$0(orcid)0000-0003-3043-147X$$aMartinez-Lostao, L$$uUniversidad de Zaragoza 000048608 245__ $$aHow Do Cytotoxic Lymphocytes Kill Cancer Cells? 000048608 260__ $$c2015 000048608 5060_ $$aAccess copy available to the general public$$fUnrestricted 000048608 5203_ $$aIn the past few years, cancer immunotherapy has emerged as a safe and effective alternative for treatment of cancers that do not respond to classical treatments, including those types with high aggressiveness. New immune modulators, such as cytokines, blockers of CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) and PD-1(programmed cell death protein 1)/PD-L1 (programmed death-ligand 1), and interaction or adoptive cell therapy, have been developed and approved to treat solid and hematologic carcinomas. In these scenarios, cytotoxic lymphocytes (CL), mainly cytotoxic T cells (Tc) and natural killer (NK) cells, are ultimately responsible for killing the cancer cells and eradicating the tumor. Extensive studies have been conducted to assess how Tc and NK cells get activated and recognize the cancer cell. In contrast, few studies have focused on the effector molecules used by CLs to kill cancer cells during cancer immunosurveillance and immunotherapy. In this article, the two main pathways involved in CL-mediated tumor cell death, granule exocytosis (perforin and granzymes) and death ligands, are briefly introduced, followed by a critical discussion of the molecules involved in cell death during cancer immunosurveillance and immunotherapy. This discussion also covers unexpected consequences of proinflammatory and survival effects of granzymes and death ligands and recent experimental evidence indicating that perforin and granzymes of CLs can activate nonapoptotic pathways of cell death, overcoming apoptosis defects and chemoresistance. The consequences of apoptosis versus other modalities of cell death for an effective treatment of cancer by modulating the patient immune system are also briefly discussed. Clin Cancer Res; 21(22); 5047–56. ©2015 AACR. 000048608 536__ $$9info:eu-repo/grantAgreement/ES/MINECO/SAF2014-54763-C2-1-R$$9info:eu-repo/grantAgreement/ES/MINECO-FEDER/SAF2011-25390$$9info:eu-repo/grantAgreement/ES/MICINN/SAF2013-48626-C2-1-R 000048608 540__ $$9info:eu-repo/semantics/openAccess$$aAll rights reserved$$uhttp://www.europeana.eu/rights/rr-f/ 000048608 590__ $$a8.738$$b2015 000048608 591__ $$aONCOLOGY$$b12 / 213 = 0.056$$c2015$$dQ1$$eT1 000048608 592__ $$a5.291$$b2015 000048608 593__ $$aOncology$$c2015$$dQ1 000048608 593__ $$aCancer Research$$c2015$$dQ1 000048608 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/acceptedVersion 000048608 700__ $$0(orcid)0000-0002-5175-8394$$aAnel, A$$uUniversidad de Zaragoza 000048608 700__ $$0(orcid)0000-0003-0154-0730$$aPardo, J.$$uUniversidad de Zaragoza 000048608 7102_ $$11008$$2566$$aUniversidad de Zaragoza$$bDpto. Microb.Med.Pr.,Sal.Públ.$$cÁrea Inmunología 000048608 7102_ $$11002$$2060$$aUniversidad de Zaragoza$$bDpto. Bioq.Biolog.Mol. Celular$$cÁrea Bioquímica y Biolog.Mole. 000048608 7102_ $$11002$$2050$$aUniversidad de Zaragoza$$bDpto. Bioq.Biolog.Mol. Celular$$cÁrea Biología Celular 000048608 773__ $$g21, 22 (2015), 5047-5056$$pClin. cancer res.$$tCLINICAL CANCER RESEARCH$$x1078-0432 000048608 8564_ $$s80695$$uhttps://zaguan.unizar.es/record/48608/files/texto_completo.pdf$$yPostprint 000048608 8564_ $$s39879$$uhttps://zaguan.unizar.es/record/48608/files/texto_completo.jpg?subformat=icon$$xicon$$yPostprint 000048608 909CO $$ooai:zaguan.unizar.es:48608$$particulos$$pdriver 000048608 951__ $$a2021-01-21-11:10:19 000048608 980__ $$aARTICLE