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Administration of fusion cytokines induces tumor regression and systemic antitumor immunity

It is difficult to improve the curative effects of cancer immunotherapy on solid tumors. Cytokines, as powerful immune regulators, show potential in activating host antitumor immunity. We have previously found that the administration of certain cytokine combinations induces complete tumor clearance....

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Autores principales: Zhang, Jinyu, Zhao, Xuan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8491205/
https://www.ncbi.nlm.nih.gov/pubmed/34766145
http://dx.doi.org/10.1002/mco2.68
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author Zhang, Jinyu
Zhao, Xuan
author_facet Zhang, Jinyu
Zhao, Xuan
author_sort Zhang, Jinyu
collection PubMed
description It is difficult to improve the curative effects of cancer immunotherapy on solid tumors. Cytokines, as powerful immune regulators, show potential in activating host antitumor immunity. We have previously found that the administration of certain cytokine combinations induces complete tumor clearance. Here, we constructed cognate fusion cytokines and evaluated their antitumor effects in various mouse tumor models. The in situ induction of the expression of the fusion cytokine IL12IL2GMCSF caused tumor eradication, including that of the tumors at advanced stages. An immune memory against unrelated syngeneic tumors was also elicited. Furthermore, flow cytometry analysis revealed that tumor‐infiltrating CD3+ cells were greatly increased in the treated tumors and were accompanied by an elevation of CD8+/CD4+ ratios. This fusion protein exhibited superior immune activating capability compared to that of cytokine mixtures, in the experiments done in vitro. We also induced tumor regression in various immunocompetent tumor models via intratumoral injection. To improve its translational potential for clinical application, a systemically‐administered immunocytokine, IL12IL2DiaNFGMCSF, was constructed by inserting a tumor‐targeting diabody in the fusion protein. This protein also displayed good immune stimulating activities in vitro. Intravenous infusion of IL12IL2DiaNFGMCSF induced tumor‐infiltrating immune cell alterations like IL12IL2GMCSF, with moderate serum IFNγ increment. Therapeutic effects were observed in the various tumor models after systemic administration of IL12IL2DiaNFGMCSF, but with slight toxicity. These results show the feasibility of developing a versatile cancer immunotherapy.
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spelling pubmed-84912052021-11-10 Administration of fusion cytokines induces tumor regression and systemic antitumor immunity Zhang, Jinyu Zhao, Xuan MedComm (2020) Original Articles It is difficult to improve the curative effects of cancer immunotherapy on solid tumors. Cytokines, as powerful immune regulators, show potential in activating host antitumor immunity. We have previously found that the administration of certain cytokine combinations induces complete tumor clearance. Here, we constructed cognate fusion cytokines and evaluated their antitumor effects in various mouse tumor models. The in situ induction of the expression of the fusion cytokine IL12IL2GMCSF caused tumor eradication, including that of the tumors at advanced stages. An immune memory against unrelated syngeneic tumors was also elicited. Furthermore, flow cytometry analysis revealed that tumor‐infiltrating CD3+ cells were greatly increased in the treated tumors and were accompanied by an elevation of CD8+/CD4+ ratios. This fusion protein exhibited superior immune activating capability compared to that of cytokine mixtures, in the experiments done in vitro. We also induced tumor regression in various immunocompetent tumor models via intratumoral injection. To improve its translational potential for clinical application, a systemically‐administered immunocytokine, IL12IL2DiaNFGMCSF, was constructed by inserting a tumor‐targeting diabody in the fusion protein. This protein also displayed good immune stimulating activities in vitro. Intravenous infusion of IL12IL2DiaNFGMCSF induced tumor‐infiltrating immune cell alterations like IL12IL2GMCSF, with moderate serum IFNγ increment. Therapeutic effects were observed in the various tumor models after systemic administration of IL12IL2DiaNFGMCSF, but with slight toxicity. These results show the feasibility of developing a versatile cancer immunotherapy. John Wiley and Sons Inc. 2021-05-04 /pmc/articles/PMC8491205/ /pubmed/34766145 http://dx.doi.org/10.1002/mco2.68 Text en © 2021 The Authors. MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd. https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Articles
Zhang, Jinyu
Zhao, Xuan
Administration of fusion cytokines induces tumor regression and systemic antitumor immunity
title Administration of fusion cytokines induces tumor regression and systemic antitumor immunity
title_full Administration of fusion cytokines induces tumor regression and systemic antitumor immunity
title_fullStr Administration of fusion cytokines induces tumor regression and systemic antitumor immunity
title_full_unstemmed Administration of fusion cytokines induces tumor regression and systemic antitumor immunity
title_short Administration of fusion cytokines induces tumor regression and systemic antitumor immunity
title_sort administration of fusion cytokines induces tumor regression and systemic antitumor immunity
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8491205/
https://www.ncbi.nlm.nih.gov/pubmed/34766145
http://dx.doi.org/10.1002/mco2.68
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AT zhaoxuan administrationoffusioncytokinesinducestumorregressionandsystemicantitumorimmunity