Cell death induced by cytotoxic CD8+ T cells is immunogenic and primes caspase-3–dependent spread immunity against endogenous tumor antigens

6 Figures

Bibliographic Details
Authors: Jaime Sánchez, Paula, Uranga Murillo, Iratxe, Aguiló, Nacho, Chayeb Khouili, Sofia, Arias, Maykel, Sancho, David, Pardo, Julián
Format: article
Status:Published version
Publication Date:2020
Country:España
Institution:Consejo Superior de Investigaciones Científicas (CSIC)
Repository:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/211313
Online Access:http://hdl.handle.net/10261/211313
Access Level:Open access
Keyword:Cytotoxic CD8+ T cells
Tumor immunology
Caspases
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spelling Cell death induced by cytotoxic CD8+ T cells is immunogenic and primes caspase-3–dependent spread immunity against endogenous tumor antigensJaime Sánchez, PaulaUranga Murillo, IratxeAguiló, NachoChayeb Khouili, SofiaArias, MaykelSancho, DavidPardo, JuliánCytotoxic CD8+ T cellsTumor immunologyCaspases6 Figures[Background] 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.The authors would like to acknowledge the use of Servicios Científico Técnicos del CIBA (IACS-Universidad de Zaragoza) and Servicios Apoyo Investigación de la Universidad de Zaragoza.Peer reviewedBMJ Publishing GroupUniversidad de ZaragozaJaime Sánchez, Paula [0000-0002-8731-4269Uranga Murillo, Iratxe [0000-0001-8411-984X]Aguiló, Nacho [0000-0001-7897-9173]Chayeb Khouili, Sofia [0000-0002-7333-789X]Arias, Maykel [0000-0002-9730-2210]Sancho, David [0000-0003-2890-3984]Pardo, Julián [0000-0003-0154-0730]Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202020202020info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/211313reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Ingléshttp://dx.doi.org/10.1136/jitc-2020-000528Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/2113132026-05-22T06:33:51Z
dc.title.none.fl_str_mv Cell death induced by cytotoxic CD8+ T cells is immunogenic and primes caspase-3–dependent spread immunity against endogenous tumor antigens
title Cell death induced by cytotoxic CD8+ T cells is immunogenic and primes caspase-3–dependent spread immunity against endogenous tumor antigens
spellingShingle Cell death induced by cytotoxic CD8+ T cells is immunogenic and primes caspase-3–dependent spread immunity against endogenous tumor antigens
Jaime Sánchez, Paula
Cytotoxic CD8+ T cells
Tumor immunology
Caspases
title_short Cell death induced by cytotoxic CD8+ T cells is immunogenic and primes caspase-3–dependent spread immunity against endogenous tumor antigens
title_full Cell death induced by cytotoxic CD8+ T cells is immunogenic and primes caspase-3–dependent spread immunity against endogenous tumor antigens
title_fullStr Cell death induced by cytotoxic CD8+ T cells is immunogenic and primes caspase-3–dependent spread immunity against endogenous tumor antigens
title_full_unstemmed Cell death induced by cytotoxic CD8+ T cells is immunogenic and primes caspase-3–dependent spread immunity against endogenous tumor antigens
title_sort Cell death induced by cytotoxic CD8+ T cells is immunogenic and primes caspase-3–dependent spread immunity against endogenous tumor antigens
dc.creator.none.fl_str_mv Jaime Sánchez, Paula
Uranga Murillo, Iratxe
Aguiló, Nacho
Chayeb Khouili, Sofia
Arias, Maykel
Sancho, David
Pardo, Julián
author Jaime Sánchez, Paula
author_facet Jaime Sánchez, Paula
Uranga Murillo, Iratxe
Aguiló, Nacho
Chayeb Khouili, Sofia
Arias, Maykel
Sancho, David
Pardo, Julián
author_role author
author2 Uranga Murillo, Iratxe
Aguiló, Nacho
Chayeb Khouili, Sofia
Arias, Maykel
Sancho, David
Pardo, Julián
author2_role author
author
author
author
author
author
dc.contributor.none.fl_str_mv Universidad de Zaragoza
Jaime Sánchez, Paula [0000-0002-8731-4269
Uranga Murillo, Iratxe [0000-0001-8411-984X]
Aguiló, Nacho [0000-0001-7897-9173]
Chayeb Khouili, Sofia [0000-0002-7333-789X]
Arias, Maykel [0000-0002-9730-2210]
Sancho, David [0000-0003-2890-3984]
Pardo, Julián [0000-0003-0154-0730]
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Cytotoxic CD8+ T cells
Tumor immunology
Caspases
topic Cytotoxic CD8+ T cells
Tumor immunology
Caspases
description 6 Figures
publishDate 2020
dc.date.none.fl_str_mv 2020
2020
2020
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/211313
url http://hdl.handle.net/10261/211313
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv http://dx.doi.org/10.1136/jitc-2020-000528
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv BMJ Publishing Group
publisher.none.fl_str_mv BMJ Publishing Group
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869406820038082560
score 15,81155

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