Intratumoral combination therapy with poly(I:C) and resiquimod synergistically triggers tumor-associated macrophages for effective systemic antitumoral immunity

Anfray, C. (Clément)|||/items/2775edb0-703b-424f-8752-b18c830077b4; Mainini, F. (Francesco)|||/items/08d679a1-5c31-4ddd-9160-040086d3fbcb; Digifico, E. (Elisabeth)|||/items/822e6af8-fa14-4c23-867e-162a5665fa0f; Maeda, A. (Akihiro)|||/items/b033a2ec-a838-4247-8da0-8c39492f28d0; Sironi, M. (Marina)|||/items/905bdd09-1ab4-456d-9b0b-eb3d7a3c1af5; Erreni, M. (Marco)|||/items/1773bc6d-2aeb-4182-bc95-88b22a1a5ce5; Anselmo, A. (Achille)|||/items/de34ae1d-30af-4e2b-b82a-a1b8f2150d30; Ummarino, A. (Aldo)|||/items/6396a02c-23bd-488e-8aa7-e91871b15776; Gandoy, S. (Sara)|||/items/7d2a402c-2004-4c99-8dec-62c5672b3961; Expósito, F. (Francisco)|||/items/df090510-428a-427f-91b4-4e9410bdaf27; Redrado, M. (Miriam)|||/items/a29b6f51-e97e-4d0a-816f-c3c3019ee27a; Serrano-Tejero, D. (Diego)|||/items/1c12ec1a-108a-4bf8-a5bd-dc8c3b89fed4; Calvo-González, A. (Alfonso)|||/items/ac176653-87d5-476b-b2b9-ade455cfa6de; Martens, M. (Marvin)|||/items/127176a0-cbc6-42eb-b1a0-d43e24d756bd; Bravo, S. (Susana B.)|||/items/e01e519b-f836-4fcb-86d7-31112734e8e2; Mantovani, A. (Alberto)|||/items/4e515d8b-09d5-4e74-b423-8a1a606cb962; Allavena, P. (Paola)|||/items/321a6fe2-7a30-4ac9-96fd-757b0d4131f4; Torres-Andón, F. (Fernando)|||/items/298b0797-b536-4739-9d9b-38502cfd16ad

Intratumoral combination therapy with poly(I:C) and resiquimod synergistically triggers tumor-associated macrophages for effective systemic antitumoral immunity

Background: Tumor-associated macrophages (TAMs) play a key immunosuppressive role that limits the ability of the immune system to fight cancer and hinder the antitumoral efficacy of most treatments currently applied in the clinic. Previous studies have evaluated the antitumoral immune response trigg...

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Autores:	Anfray, C. (Clément)\|\|\|/items/2775edb0-703b-424f-8752-b18c830077b4, Mainini, F. (Francesco)\|\|\|/items/08d679a1-5c31-4ddd-9160-040086d3fbcb, Digifico, E. (Elisabeth)\|\|\|/items/822e6af8-fa14-4c23-867e-162a5665fa0f, Maeda, A. (Akihiro)\|\|\|/items/b033a2ec-a838-4247-8da0-8c39492f28d0, Sironi, M. (Marina)\|\|\|/items/905bdd09-1ab4-456d-9b0b-eb3d7a3c1af5, Erreni, M. (Marco)\|\|\|/items/1773bc6d-2aeb-4182-bc95-88b22a1a5ce5, Anselmo, A. (Achille)\|\|\|/items/de34ae1d-30af-4e2b-b82a-a1b8f2150d30, Ummarino, A. (Aldo)\|\|\|/items/6396a02c-23bd-488e-8aa7-e91871b15776, Gandoy, S. (Sara)\|\|\|/items/7d2a402c-2004-4c99-8dec-62c5672b3961, Expósito, F. (Francisco)\|\|\|/items/df090510-428a-427f-91b4-4e9410bdaf27, Redrado, M. (Miriam)\|\|\|/items/a29b6f51-e97e-4d0a-816f-c3c3019ee27a, Serrano-Tejero, D. (Diego)\|\|\|/items/1c12ec1a-108a-4bf8-a5bd-dc8c3b89fed4, Calvo-González, A. (Alfonso)\|\|\|/items/ac176653-87d5-476b-b2b9-ade455cfa6de, Martens, M. (Marvin)\|\|\|/items/127176a0-cbc6-42eb-b1a0-d43e24d756bd, Bravo, S. (Susana B.)\|\|\|/items/e01e519b-f836-4fcb-86d7-31112734e8e2, Mantovani, A. (Alberto)\|\|\|/items/4e515d8b-09d5-4e74-b423-8a1a606cb962, Allavena, P. (Paola)\|\|\|/items/321a6fe2-7a30-4ac9-96fd-757b0d4131f4, Torres-Andón, F. (Fernando)\|\|\|/items/298b0797-b536-4739-9d9b-38502cfd16ad
Tipo de recurso:	artículo
Fecha de publicación:	2021
País:	España
Institución:	Universidad de Navarra
Repositorio:	Dadun. Depósito Académico Digital de la Universidad de Navarra
Idioma:	inglés
OAI Identifier:	oai:dadun.unav.edu:10171/112582
Acceso en línea:	https://hdl.handle.net/10171/112582
Access Level:	acceso abierto
Palabra clave:	Immunity Immunotherapy Innate Lung neoplasms Macrophages

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network_acronym_str	ES
network_name_str	España
repository_id_str
dc.title.none.fl_str_mv	Intratumoral combination therapy with poly(I:C) and resiquimod synergistically triggers tumor-associated macrophages for effective systemic antitumoral immunity
title	Intratumoral combination therapy with poly(I:C) and resiquimod synergistically triggers tumor-associated macrophages for effective systemic antitumoral immunity
spellingShingle	Intratumoral combination therapy with poly(I:C) and resiquimod synergistically triggers tumor-associated macrophages for effective systemic antitumoral immunity Anfray, C. (Clément)\|\|\|/items/2775edb0-703b-424f-8752-b18c830077b4 Immunity Immunotherapy Innate Lung neoplasms Macrophages
title_short	Intratumoral combination therapy with poly(I:C) and resiquimod synergistically triggers tumor-associated macrophages for effective systemic antitumoral immunity
title_full	Intratumoral combination therapy with poly(I:C) and resiquimod synergistically triggers tumor-associated macrophages for effective systemic antitumoral immunity
title_fullStr	Intratumoral combination therapy with poly(I:C) and resiquimod synergistically triggers tumor-associated macrophages for effective systemic antitumoral immunity
title_full_unstemmed	Intratumoral combination therapy with poly(I:C) and resiquimod synergistically triggers tumor-associated macrophages for effective systemic antitumoral immunity
title_sort	Intratumoral combination therapy with poly(I:C) and resiquimod synergistically triggers tumor-associated macrophages for effective systemic antitumoral immunity
dc.creator.none.fl_str_mv	Anfray, C. (Clément)\|\|\|/items/2775edb0-703b-424f-8752-b18c830077b4 Mainini, F. (Francesco)\|\|\|/items/08d679a1-5c31-4ddd-9160-040086d3fbcb Digifico, E. (Elisabeth)\|\|\|/items/822e6af8-fa14-4c23-867e-162a5665fa0f Maeda, A. (Akihiro)\|\|\|/items/b033a2ec-a838-4247-8da0-8c39492f28d0 Sironi, M. (Marina)\|\|\|/items/905bdd09-1ab4-456d-9b0b-eb3d7a3c1af5 Erreni, M. (Marco)\|\|\|/items/1773bc6d-2aeb-4182-bc95-88b22a1a5ce5 Anselmo, A. (Achille)\|\|\|/items/de34ae1d-30af-4e2b-b82a-a1b8f2150d30 Ummarino, A. (Aldo)\|\|\|/items/6396a02c-23bd-488e-8aa7-e91871b15776 Gandoy, S. (Sara)\|\|\|/items/7d2a402c-2004-4c99-8dec-62c5672b3961 Expósito, F. (Francisco)\|\|\|/items/df090510-428a-427f-91b4-4e9410bdaf27 Redrado, M. (Miriam)\|\|\|/items/a29b6f51-e97e-4d0a-816f-c3c3019ee27a Serrano-Tejero, D. (Diego)\|\|\|/items/1c12ec1a-108a-4bf8-a5bd-dc8c3b89fed4 Calvo-González, A. (Alfonso)\|\|\|/items/ac176653-87d5-476b-b2b9-ade455cfa6de Martens, M. (Marvin)\|\|\|/items/127176a0-cbc6-42eb-b1a0-d43e24d756bd Bravo, S. (Susana B.)\|\|\|/items/e01e519b-f836-4fcb-86d7-31112734e8e2 Mantovani, A. (Alberto)\|\|\|/items/4e515d8b-09d5-4e74-b423-8a1a606cb962 Allavena, P. (Paola)\|\|\|/items/321a6fe2-7a30-4ac9-96fd-757b0d4131f4 Torres-Andón, F. (Fernando)\|\|\|/items/298b0797-b536-4739-9d9b-38502cfd16ad
author	Anfray, C. (Clément)\|\|\|/items/2775edb0-703b-424f-8752-b18c830077b4
author_facet	Anfray, C. (Clément)\|\|\|/items/2775edb0-703b-424f-8752-b18c830077b4 Mainini, F. (Francesco)\|\|\|/items/08d679a1-5c31-4ddd-9160-040086d3fbcb Digifico, E. (Elisabeth)\|\|\|/items/822e6af8-fa14-4c23-867e-162a5665fa0f Maeda, A. (Akihiro)\|\|\|/items/b033a2ec-a838-4247-8da0-8c39492f28d0 Sironi, M. (Marina)\|\|\|/items/905bdd09-1ab4-456d-9b0b-eb3d7a3c1af5 Erreni, M. (Marco)\|\|\|/items/1773bc6d-2aeb-4182-bc95-88b22a1a5ce5 Anselmo, A. (Achille)\|\|\|/items/de34ae1d-30af-4e2b-b82a-a1b8f2150d30 Ummarino, A. (Aldo)\|\|\|/items/6396a02c-23bd-488e-8aa7-e91871b15776 Gandoy, S. (Sara)\|\|\|/items/7d2a402c-2004-4c99-8dec-62c5672b3961 Expósito, F. (Francisco)\|\|\|/items/df090510-428a-427f-91b4-4e9410bdaf27 Redrado, M. (Miriam)\|\|\|/items/a29b6f51-e97e-4d0a-816f-c3c3019ee27a Serrano-Tejero, D. (Diego)\|\|\|/items/1c12ec1a-108a-4bf8-a5bd-dc8c3b89fed4 Calvo-González, A. (Alfonso)\|\|\|/items/ac176653-87d5-476b-b2b9-ade455cfa6de Martens, M. (Marvin)\|\|\|/items/127176a0-cbc6-42eb-b1a0-d43e24d756bd Bravo, S. (Susana B.)\|\|\|/items/e01e519b-f836-4fcb-86d7-31112734e8e2 Mantovani, A. (Alberto)\|\|\|/items/4e515d8b-09d5-4e74-b423-8a1a606cb962 Allavena, P. (Paola)\|\|\|/items/321a6fe2-7a30-4ac9-96fd-757b0d4131f4 Torres-Andón, F. (Fernando)\|\|\|/items/298b0797-b536-4739-9d9b-38502cfd16ad
author_role	author
author2	Mainini, F. (Francesco)\|\|\|/items/08d679a1-5c31-4ddd-9160-040086d3fbcb Digifico, E. (Elisabeth)\|\|\|/items/822e6af8-fa14-4c23-867e-162a5665fa0f Maeda, A. (Akihiro)\|\|\|/items/b033a2ec-a838-4247-8da0-8c39492f28d0 Sironi, M. (Marina)\|\|\|/items/905bdd09-1ab4-456d-9b0b-eb3d7a3c1af5 Erreni, M. (Marco)\|\|\|/items/1773bc6d-2aeb-4182-bc95-88b22a1a5ce5 Anselmo, A. (Achille)\|\|\|/items/de34ae1d-30af-4e2b-b82a-a1b8f2150d30 Ummarino, A. (Aldo)\|\|\|/items/6396a02c-23bd-488e-8aa7-e91871b15776 Gandoy, S. (Sara)\|\|\|/items/7d2a402c-2004-4c99-8dec-62c5672b3961 Expósito, F. (Francisco)\|\|\|/items/df090510-428a-427f-91b4-4e9410bdaf27 Redrado, M. (Miriam)\|\|\|/items/a29b6f51-e97e-4d0a-816f-c3c3019ee27a Serrano-Tejero, D. (Diego)\|\|\|/items/1c12ec1a-108a-4bf8-a5bd-dc8c3b89fed4 Calvo-González, A. (Alfonso)\|\|\|/items/ac176653-87d5-476b-b2b9-ade455cfa6de Martens, M. (Marvin)\|\|\|/items/127176a0-cbc6-42eb-b1a0-d43e24d756bd Bravo, S. (Susana B.)\|\|\|/items/e01e519b-f836-4fcb-86d7-31112734e8e2 Mantovani, A. (Alberto)\|\|\|/items/4e515d8b-09d5-4e74-b423-8a1a606cb962 Allavena, P. (Paola)\|\|\|/items/321a6fe2-7a30-4ac9-96fd-757b0d4131f4 Torres-Andón, F. (Fernando)\|\|\|/items/298b0797-b536-4739-9d9b-38502cfd16ad
author2_role	author author author author author author author author author author author author author author author author author
dc.contributor.none.fl_str_mv	Dadun. Depósito Académico Digital Universidad de Navarra
dc.subject.none.fl_str_mv	Immunity Immunotherapy Innate Lung neoplasms Macrophages
topic	Immunity Immunotherapy Innate Lung neoplasms Macrophages
description	Background: Tumor-associated macrophages (TAMs) play a key immunosuppressive role that limits the ability of the immune system to fight cancer and hinder the antitumoral efficacy of most treatments currently applied in the clinic. Previous studies have evaluated the antitumoral immune response triggered by (TLR) agonists, such as poly(I:C), imiquimod (R837) or resiquimod (R848) as monotherapies; however, their combination for the treatment of cancer has not been explored. This study investigates the antitumoral efficacy and the macrophage reprogramming triggered by poly(I:C) combined with R848 or with R837, versus single treatments. Methods: TLR agonist treatments were evaluated in vitro for toxicity and immunostimulatory activity by Alamar Blue, ELISA and flow cytometry using primary human and murine M-CSF-differentiated macrophages. Cytotoxic activity of TLR-treated macrophages toward cancer cells was evaluated with an in vitro functional assay by flow cytometry. For in vivo experiments, the CMT167 lung cancer model and the MN/MCA1 fibrosarcoma model metastasizing to lungs were used; tumor-infiltrating leukocytes were evaluated by flow cytometry, RT-qPCR, multispectral immunophenotyping, quantitative proteomic experiments, and protein-protein interaction analysis. Results: Results demonstrated the higher efficacy of poly(I:C) combined with R848 versus single treatments or combined with R837 to polarize macrophages toward M1-like antitumor effectors in vitro. In vivo, the intratumoral synergistic combination of poly(I:C)+R848 significantly prevented tumor growth and metastasis in lung cancer and fibrosarcoma immunocompetent murine models. Regressing tumors showed increased infiltration of macrophages with a higher M1:M2 ratio, recruitment of CD4+ and CD8+ T cells, accompanied by a reduction of immunosuppressive CD206+ TAMs and FOXP3+/CD4+ T cells. The depletion of both CD4+ and CD8+ T cells resulted in complete loss of treatment efficacy. Treated mice acquired systemic antitumoral response and resistance to tumor rechallenge mediated by boosted macrophage cytotoxic activity and T-cell proliferation. Proteomic experiments validate the superior activation of innate immunity by poly(I:C)+R848 combination versus single treatments or poly(I:C)+R837, and protein-protein-interaction network analysis reveal the key activation of the STAT1 pathway. Discussion: These findings demonstrate the antitumor immune responses mediated by macrophage activation on local administration of poly(I:C)+R848 combination and support the intratumoral application of this therapy to patients with solid tumors in the clinic.
publishDate	2021
dc.date.none.fl_str_mv	2021 2021-01-01 2021 2021-01-01
dc.type.none.fl_str_mv	journal article http://purl.org/coar/resource_type/c_6501
dc.type.openaire.fl_str_mv	info:eu-repo/semantics/article
format	article
dc.identifier.none.fl_str_mv	https://hdl.handle.net/10171/112582
url	https://hdl.handle.net/10171/112582
dc.language.none.fl_str_mv	Inglés eng
language_invalid_str_mv	Inglés
language	eng
dc.rights.none.fl_str_mv	open access http://purl.org/coar/access_right/c_abf2
dc.rights.openaire.fl_str_mv	info:eu-repo/semantics/openAccess
rights_invalid_str_mv	open access http://purl.org/coar/access_right/c_abf2
eu_rights_str_mv	openAccess
dc.format.none.fl_str_mv	application/pdf
dc.publisher.none.fl_str_mv	BMJ
publisher.none.fl_str_mv	BMJ
dc.source.none.fl_str_mv	reponame:Dadun. Depósito Académico Digital de la Universidad de Navarra instname:Universidad de Navarra
instname_str	Universidad de Navarra
reponame_str	Dadun. Depósito Académico Digital de la Universidad de Navarra
collection	Dadun. Depósito Académico Digital de la Universidad de Navarra
repository.name.fl_str_mv
repository.mail.fl_str_mv
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spelling	Intratumoral combination therapy with poly(I:C) and resiquimod synergistically triggers tumor-associated macrophages for effective systemic antitumoral immunityAnfray, C. (Clément)\|\|\|/items/2775edb0-703b-424f-8752-b18c830077b4Mainini, F. (Francesco)\|\|\|/items/08d679a1-5c31-4ddd-9160-040086d3fbcbDigifico, E. (Elisabeth)\|\|\|/items/822e6af8-fa14-4c23-867e-162a5665fa0fMaeda, A. (Akihiro)\|\|\|/items/b033a2ec-a838-4247-8da0-8c39492f28d0Sironi, M. (Marina)\|\|\|/items/905bdd09-1ab4-456d-9b0b-eb3d7a3c1af5Erreni, M. (Marco)\|\|\|/items/1773bc6d-2aeb-4182-bc95-88b22a1a5ce5Anselmo, A. (Achille)\|\|\|/items/de34ae1d-30af-4e2b-b82a-a1b8f2150d30Ummarino, A. (Aldo)\|\|\|/items/6396a02c-23bd-488e-8aa7-e91871b15776Gandoy, S. (Sara)\|\|\|/items/7d2a402c-2004-4c99-8dec-62c5672b3961Expósito, F. (Francisco)\|\|\|/items/df090510-428a-427f-91b4-4e9410bdaf27Redrado, M. (Miriam)\|\|\|/items/a29b6f51-e97e-4d0a-816f-c3c3019ee27aSerrano-Tejero, D. (Diego)\|\|\|/items/1c12ec1a-108a-4bf8-a5bd-dc8c3b89fed4Calvo-González, A. (Alfonso)\|\|\|/items/ac176653-87d5-476b-b2b9-ade455cfa6deMartens, M. (Marvin)\|\|\|/items/127176a0-cbc6-42eb-b1a0-d43e24d756bdBravo, S. (Susana B.)\|\|\|/items/e01e519b-f836-4fcb-86d7-31112734e8e2Mantovani, A. (Alberto)\|\|\|/items/4e515d8b-09d5-4e74-b423-8a1a606cb962Allavena, P. (Paola)\|\|\|/items/321a6fe2-7a30-4ac9-96fd-757b0d4131f4Torres-Andón, F. (Fernando)\|\|\|/items/298b0797-b536-4739-9d9b-38502cfd16adImmunityImmunotherapyInnateLung neoplasmsMacrophagesBackground: Tumor-associated macrophages (TAMs) play a key immunosuppressive role that limits the ability of the immune system to fight cancer and hinder the antitumoral efficacy of most treatments currently applied in the clinic. Previous studies have evaluated the antitumoral immune response triggered by (TLR) agonists, such as poly(I:C), imiquimod (R837) or resiquimod (R848) as monotherapies; however, their combination for the treatment of cancer has not been explored. This study investigates the antitumoral efficacy and the macrophage reprogramming triggered by poly(I:C) combined with R848 or with R837, versus single treatments. Methods: TLR agonist treatments were evaluated in vitro for toxicity and immunostimulatory activity by Alamar Blue, ELISA and flow cytometry using primary human and murine M-CSF-differentiated macrophages. Cytotoxic activity of TLR-treated macrophages toward cancer cells was evaluated with an in vitro functional assay by flow cytometry. For in vivo experiments, the CMT167 lung cancer model and the MN/MCA1 fibrosarcoma model metastasizing to lungs were used; tumor-infiltrating leukocytes were evaluated by flow cytometry, RT-qPCR, multispectral immunophenotyping, quantitative proteomic experiments, and protein-protein interaction analysis. Results: Results demonstrated the higher efficacy of poly(I:C) combined with R848 versus single treatments or combined with R837 to polarize macrophages toward M1-like antitumor effectors in vitro. In vivo, the intratumoral synergistic combination of poly(I:C)+R848 significantly prevented tumor growth and metastasis in lung cancer and fibrosarcoma immunocompetent murine models. Regressing tumors showed increased infiltration of macrophages with a higher M1:M2 ratio, recruitment of CD4+ and CD8+ T cells, accompanied by a reduction of immunosuppressive CD206+ TAMs and FOXP3+/CD4+ T cells. The depletion of both CD4+ and CD8+ T cells resulted in complete loss of treatment efficacy. Treated mice acquired systemic antitumoral response and resistance to tumor rechallenge mediated by boosted macrophage cytotoxic activity and T-cell proliferation. Proteomic experiments validate the superior activation of innate immunity by poly(I:C)+R848 combination versus single treatments or poly(I:C)+R837, and protein-protein-interaction network analysis reveal the key activation of the STAT1 pathway. Discussion: These findings demonstrate the antitumor immune responses mediated by macrophage activation on local administration of poly(I:C)+R848 combination and support the intratumoral application of this therapy to patients with solid tumors in the clinic.BMJDadun. Depósito Académico Digital Universidad de Navarra20212021-01-0120212021-01-01journal articlehttp://purl.org/coar/resource_type/c_6501info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/10171/112582reponame:Dadun. Depósito Académico Digital de la Universidad de Navarrainstname:Universidad de NavarraInglésengopen accesshttp://purl.org/coar/access_right/c_abf2info:eu-repo/semantics/openAccessoai:dadun.unav.edu:10171/1125822026-06-21T12:47:57Z
score	15,811543

Intratumoral combination therapy with poly(I:C) and resiquimod synergistically triggers tumor-associated macrophages for effective systemic antitumoral immunity

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