Improvement of antitumor therapies based on vaccines and immune-checkpoint inhibitors by counteracting tumor-immunostimulationw

Autores
Chiarella, Paula; Vermeulen, Elba Monica; Montagna, Daniela Romina; Vallecorsa, Pablo Daniel; Strazza, Ariel Ramiro; Meiss, Roberto P.; Bustuoabad, Oscar David; Ruggiero, Raul Alejandro; Prehn, Richmond T.
Año de publicación
2018
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Immune-checkpoint inhibitors and antitumor vaccines may produce both tumor-inhibitory and tumor-stimulatory effects on growing tumors depending on the stage of tumor growth at which treatment is initiated. These paradoxical results are not necessarily incompatible with current tumor immunology but they might better be explained assuming the involvement of the phenomenon of tumor immunostimulation. This phenomenon was originally postulated on the basis that the immune response (IR) evoked in Winn tests by strong chemical murine tumors was not linear but biphasic, with strong IR producing inhibition and weak IR inducing stimulation of tumor growth. Herein, we extended those former observations to weak spontaneous murine tumors growing in pre-immunized, immune-competent and immune-depressed mice. Furthermore, we demonstrated that the interaction of specifical T cells and target tumor cells at low stimulatory ratios enhanced the production of chemokines aimed to recruit macrophages at the tumor site, which, upon activation of toll-like receptor 4 and p38 signaling pathways, would recruit and activate more macrophages and other inflammatory cells which would produce growth-stimulating signals leading to an accelerated tumor growth. On this basis, the paradoxical effects achieved by immunological therapies on growing tumors could be explained depending upon where the therapy-induced IR stands on the biphasic IR curve at each stage of tumor growth. At stages where tumor growth was enhanced (medium and large-sized tumors), counteraction of the tumor-immunostimulatory effect with anti-inflammatory strategies or, more efficiently, with selective inhibitors of p38 signaling pathways enabled the otherwise tumor-promoting immunological strategies to produce significant inhibition of tumor growth.
Fil: Chiarella, Paula. Academia Nacional de Medicina de Buenos Aires; Argentina
Fil: Vermeulen, Mónica. Academia Nacional de Medicina de Buenos Aires; Argentina
Fil: Montagna, Daniela R.. Academia Nacional de Medicina de Buenos Aires; Argentina
Fil: Vallecorsa, Pablo. Academia Nacional de Medicina de Buenos Aires; Argentina
Fil: Strazza, Ariel Ramiro. Academia Nacional de Medicina de Buenos Aires; Argentina
Fil: Meiss, Roberto P.. Academia Nacional de Medicina de Buenos Aires; Argentina
Fil: Bustuoabad, Oscar D.. Retired; Argentina
Fil: Ruggiero, Raúl A.. Academia Nacional de Medicina de Buenos Aires; Argentina
Fil: Prehn, Richmond T.. University Of Washington, Seattle;
Materia
ANTITUMOR VACCINES
IMMUNE-CHECKPOINTS INHIBITORS
IMMUNOSURVEILLANCE
MURINE TUMORS
TUMOR-IMMUNOSTIMULATION
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/95994

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network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Improvement of antitumor therapies based on vaccines and immune-checkpoint inhibitors by counteracting tumor-immunostimulationwChiarella, PaulaVermeulen, Elba MonicaMontagna, Daniela RominaVallecorsa, Pablo DanielStrazza, Ariel RamiroMeiss, Roberto P.Bustuoabad, Oscar DavidRuggiero, Raul AlejandroPrehn, Richmond T.ANTITUMOR VACCINESIMMUNE-CHECKPOINTS INHIBITORSIMMUNOSURVEILLANCEMURINE TUMORSTUMOR-IMMUNOSTIMULATIONhttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Immune-checkpoint inhibitors and antitumor vaccines may produce both tumor-inhibitory and tumor-stimulatory effects on growing tumors depending on the stage of tumor growth at which treatment is initiated. These paradoxical results are not necessarily incompatible with current tumor immunology but they might better be explained assuming the involvement of the phenomenon of tumor immunostimulation. This phenomenon was originally postulated on the basis that the immune response (IR) evoked in Winn tests by strong chemical murine tumors was not linear but biphasic, with strong IR producing inhibition and weak IR inducing stimulation of tumor growth. Herein, we extended those former observations to weak spontaneous murine tumors growing in pre-immunized, immune-competent and immune-depressed mice. Furthermore, we demonstrated that the interaction of specifical T cells and target tumor cells at low stimulatory ratios enhanced the production of chemokines aimed to recruit macrophages at the tumor site, which, upon activation of toll-like receptor 4 and p38 signaling pathways, would recruit and activate more macrophages and other inflammatory cells which would produce growth-stimulating signals leading to an accelerated tumor growth. On this basis, the paradoxical effects achieved by immunological therapies on growing tumors could be explained depending upon where the therapy-induced IR stands on the biphasic IR curve at each stage of tumor growth. At stages where tumor growth was enhanced (medium and large-sized tumors), counteraction of the tumor-immunostimulatory effect with anti-inflammatory strategies or, more efficiently, with selective inhibitors of p38 signaling pathways enabled the otherwise tumor-promoting immunological strategies to produce significant inhibition of tumor growth.Fil: Chiarella, Paula. Academia Nacional de Medicina de Buenos Aires; ArgentinaFil: Vermeulen, Mónica. Academia Nacional de Medicina de Buenos Aires; ArgentinaFil: Montagna, Daniela R.. Academia Nacional de Medicina de Buenos Aires; ArgentinaFil: Vallecorsa, Pablo. Academia Nacional de Medicina de Buenos Aires; ArgentinaFil: Strazza, Ariel Ramiro. Academia Nacional de Medicina de Buenos Aires; ArgentinaFil: Meiss, Roberto P.. Academia Nacional de Medicina de Buenos Aires; ArgentinaFil: Bustuoabad, Oscar D.. Retired; ArgentinaFil: Ruggiero, Raúl A.. Academia Nacional de Medicina de Buenos Aires; ArgentinaFil: Prehn, Richmond T.. University Of Washington, Seattle;Frontiers Media S.A.2018-01info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/95994Chiarella, Paula; Vermeulen, Elba Monica; Montagna, Daniela Romina; Vallecorsa, Pablo Daniel; Strazza, Ariel Ramiro; et al.; Improvement of antitumor therapies based on vaccines and immune-checkpoint inhibitors by counteracting tumor-immunostimulationw; Frontiers Media S.A.; Frontiers in Oncology; 8; 1-2018; 1-132234-943XCONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/http://journal.frontiersin.org/article/10.3389/fonc.2018.00006/fullinfo:eu-repo/semantics/altIdentifier/doi/10.3389/fonc.2018.00006info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:28:23Zoai:ri.conicet.gov.ar:11336/95994instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 10:28:23.687CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Improvement of antitumor therapies based on vaccines and immune-checkpoint inhibitors by counteracting tumor-immunostimulationw
title Improvement of antitumor therapies based on vaccines and immune-checkpoint inhibitors by counteracting tumor-immunostimulationw
spellingShingle Improvement of antitumor therapies based on vaccines and immune-checkpoint inhibitors by counteracting tumor-immunostimulationw
Chiarella, Paula
ANTITUMOR VACCINES
IMMUNE-CHECKPOINTS INHIBITORS
IMMUNOSURVEILLANCE
MURINE TUMORS
TUMOR-IMMUNOSTIMULATION
title_short Improvement of antitumor therapies based on vaccines and immune-checkpoint inhibitors by counteracting tumor-immunostimulationw
title_full Improvement of antitumor therapies based on vaccines and immune-checkpoint inhibitors by counteracting tumor-immunostimulationw
title_fullStr Improvement of antitumor therapies based on vaccines and immune-checkpoint inhibitors by counteracting tumor-immunostimulationw
title_full_unstemmed Improvement of antitumor therapies based on vaccines and immune-checkpoint inhibitors by counteracting tumor-immunostimulationw
title_sort Improvement of antitumor therapies based on vaccines and immune-checkpoint inhibitors by counteracting tumor-immunostimulationw
dc.creator.none.fl_str_mv Chiarella, Paula
Vermeulen, Elba Monica
Montagna, Daniela Romina
Vallecorsa, Pablo Daniel
Strazza, Ariel Ramiro
Meiss, Roberto P.
Bustuoabad, Oscar David
Ruggiero, Raul Alejandro
Prehn, Richmond T.
author Chiarella, Paula
author_facet Chiarella, Paula
Vermeulen, Elba Monica
Montagna, Daniela Romina
Vallecorsa, Pablo Daniel
Strazza, Ariel Ramiro
Meiss, Roberto P.
Bustuoabad, Oscar David
Ruggiero, Raul Alejandro
Prehn, Richmond T.
author_role author
author2 Vermeulen, Elba Monica
Montagna, Daniela Romina
Vallecorsa, Pablo Daniel
Strazza, Ariel Ramiro
Meiss, Roberto P.
Bustuoabad, Oscar David
Ruggiero, Raul Alejandro
Prehn, Richmond T.
author2_role author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv ANTITUMOR VACCINES
IMMUNE-CHECKPOINTS INHIBITORS
IMMUNOSURVEILLANCE
MURINE TUMORS
TUMOR-IMMUNOSTIMULATION
topic ANTITUMOR VACCINES
IMMUNE-CHECKPOINTS INHIBITORS
IMMUNOSURVEILLANCE
MURINE TUMORS
TUMOR-IMMUNOSTIMULATION
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Immune-checkpoint inhibitors and antitumor vaccines may produce both tumor-inhibitory and tumor-stimulatory effects on growing tumors depending on the stage of tumor growth at which treatment is initiated. These paradoxical results are not necessarily incompatible with current tumor immunology but they might better be explained assuming the involvement of the phenomenon of tumor immunostimulation. This phenomenon was originally postulated on the basis that the immune response (IR) evoked in Winn tests by strong chemical murine tumors was not linear but biphasic, with strong IR producing inhibition and weak IR inducing stimulation of tumor growth. Herein, we extended those former observations to weak spontaneous murine tumors growing in pre-immunized, immune-competent and immune-depressed mice. Furthermore, we demonstrated that the interaction of specifical T cells and target tumor cells at low stimulatory ratios enhanced the production of chemokines aimed to recruit macrophages at the tumor site, which, upon activation of toll-like receptor 4 and p38 signaling pathways, would recruit and activate more macrophages and other inflammatory cells which would produce growth-stimulating signals leading to an accelerated tumor growth. On this basis, the paradoxical effects achieved by immunological therapies on growing tumors could be explained depending upon where the therapy-induced IR stands on the biphasic IR curve at each stage of tumor growth. At stages where tumor growth was enhanced (medium and large-sized tumors), counteraction of the tumor-immunostimulatory effect with anti-inflammatory strategies or, more efficiently, with selective inhibitors of p38 signaling pathways enabled the otherwise tumor-promoting immunological strategies to produce significant inhibition of tumor growth.
Fil: Chiarella, Paula. Academia Nacional de Medicina de Buenos Aires; Argentina
Fil: Vermeulen, Mónica. Academia Nacional de Medicina de Buenos Aires; Argentina
Fil: Montagna, Daniela R.. Academia Nacional de Medicina de Buenos Aires; Argentina
Fil: Vallecorsa, Pablo. Academia Nacional de Medicina de Buenos Aires; Argentina
Fil: Strazza, Ariel Ramiro. Academia Nacional de Medicina de Buenos Aires; Argentina
Fil: Meiss, Roberto P.. Academia Nacional de Medicina de Buenos Aires; Argentina
Fil: Bustuoabad, Oscar D.. Retired; Argentina
Fil: Ruggiero, Raúl A.. Academia Nacional de Medicina de Buenos Aires; Argentina
Fil: Prehn, Richmond T.. University Of Washington, Seattle;
description Immune-checkpoint inhibitors and antitumor vaccines may produce both tumor-inhibitory and tumor-stimulatory effects on growing tumors depending on the stage of tumor growth at which treatment is initiated. These paradoxical results are not necessarily incompatible with current tumor immunology but they might better be explained assuming the involvement of the phenomenon of tumor immunostimulation. This phenomenon was originally postulated on the basis that the immune response (IR) evoked in Winn tests by strong chemical murine tumors was not linear but biphasic, with strong IR producing inhibition and weak IR inducing stimulation of tumor growth. Herein, we extended those former observations to weak spontaneous murine tumors growing in pre-immunized, immune-competent and immune-depressed mice. Furthermore, we demonstrated that the interaction of specifical T cells and target tumor cells at low stimulatory ratios enhanced the production of chemokines aimed to recruit macrophages at the tumor site, which, upon activation of toll-like receptor 4 and p38 signaling pathways, would recruit and activate more macrophages and other inflammatory cells which would produce growth-stimulating signals leading to an accelerated tumor growth. On this basis, the paradoxical effects achieved by immunological therapies on growing tumors could be explained depending upon where the therapy-induced IR stands on the biphasic IR curve at each stage of tumor growth. At stages where tumor growth was enhanced (medium and large-sized tumors), counteraction of the tumor-immunostimulatory effect with anti-inflammatory strategies or, more efficiently, with selective inhibitors of p38 signaling pathways enabled the otherwise tumor-promoting immunological strategies to produce significant inhibition of tumor growth.
publishDate 2018
dc.date.none.fl_str_mv 2018-01
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/95994
Chiarella, Paula; Vermeulen, Elba Monica; Montagna, Daniela Romina; Vallecorsa, Pablo Daniel; Strazza, Ariel Ramiro; et al.; Improvement of antitumor therapies based on vaccines and immune-checkpoint inhibitors by counteracting tumor-immunostimulationw; Frontiers Media S.A.; Frontiers in Oncology; 8; 1-2018; 1-13
2234-943X
CONICET Digital
CONICET
url http://hdl.handle.net/11336/95994
identifier_str_mv Chiarella, Paula; Vermeulen, Elba Monica; Montagna, Daniela Romina; Vallecorsa, Pablo Daniel; Strazza, Ariel Ramiro; et al.; Improvement of antitumor therapies based on vaccines and immune-checkpoint inhibitors by counteracting tumor-immunostimulationw; Frontiers Media S.A.; Frontiers in Oncology; 8; 1-2018; 1-13
2234-943X
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/http://journal.frontiersin.org/article/10.3389/fonc.2018.00006/full
info:eu-repo/semantics/altIdentifier/doi/10.3389/fonc.2018.00006
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Frontiers Media S.A.
publisher.none.fl_str_mv Frontiers Media S.A.
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.070432