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Intra-Tumoral Delivery of IL-27 Using Adeno-Associated Virus Stimulates Anti-tumor Immunity and Enhances the Efficacy of Immunotherapy
IL-27 is an anti-inflammatory cytokine that has been shown to have potent anti-tumor activity. We recently reported that systemic delivery of IL-27 using recombinant adeno-associated virus (rAAV) induced depletion of Tregs and significantly enhanced the efficacy of cancer immunotherapy in a variety...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2020
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7118910/ https://www.ncbi.nlm.nih.gov/pubmed/32292786 http://dx.doi.org/10.3389/fcell.2020.00210 |
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author | Hu, Aiyan Ding, Miao Zhu, Jianmin Liu, Jin-Qing Pan, Xueliang Ghoshal, Kalpana Bai, Xue-Feng |
author_facet | Hu, Aiyan Ding, Miao Zhu, Jianmin Liu, Jin-Qing Pan, Xueliang Ghoshal, Kalpana Bai, Xue-Feng |
author_sort | Hu, Aiyan |
collection | PubMed |
description | IL-27 is an anti-inflammatory cytokine that has been shown to have potent anti-tumor activity. We recently reported that systemic delivery of IL-27 using recombinant adeno-associated virus (rAAV) induced depletion of Tregs and significantly enhanced the efficacy of cancer immunotherapy in a variety of mouse tumor models. A potential caveat of systemic delivery of IL-27 using rAAV is that there is no practical method to terminate IL-27 production when its biological activity is no longer needed. Therefore, in this work, we tested if directly injecting AAV-IL-27 into tumors could lead to similar anti-tumor effect yet avoiding uncontrolled IL-27 production. We found that high levels of IL-27 was produced in tumors and released to peripheral blood after AAV-IL-27 intra-tumoral injection. AAV-IL-27 local therapy showed potent anti-tumor activity in mice bearing plasmacytoma J558 tumors and modest anti-tumor activity in mice bearing B16.F10 tumors. Intra-tumoral injection of AAV-IL-27 induced infiltration of immune effectors including CD8(+) T cells and NK cells into tumors, caused systemic reduction of Tregs and stimulated protective immunity. Mechanistically, we found that IL-27 induced T cell expression of CXCR3 in an IL-27R-dependent manner. Additionally, we found that AAV-IL-27 local therapy had significant synergy with anti-PD-1 or T cell adoptive transfer therapy. Importantly, in mice whose tumors were completely rejected, IL-27 serum levels were significantly reduced or diminished. Thus, intra-tumoral injection of AAV-IL-27 is a feasible approach that can be used alone and in combination with anti-PD-1 antibody or T cell adoptive transfer for the treatment of cancer. |
format | Online Article Text |
id | pubmed-7118910 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-71189102020-04-14 Intra-Tumoral Delivery of IL-27 Using Adeno-Associated Virus Stimulates Anti-tumor Immunity and Enhances the Efficacy of Immunotherapy Hu, Aiyan Ding, Miao Zhu, Jianmin Liu, Jin-Qing Pan, Xueliang Ghoshal, Kalpana Bai, Xue-Feng Front Cell Dev Biol Cell and Developmental Biology IL-27 is an anti-inflammatory cytokine that has been shown to have potent anti-tumor activity. We recently reported that systemic delivery of IL-27 using recombinant adeno-associated virus (rAAV) induced depletion of Tregs and significantly enhanced the efficacy of cancer immunotherapy in a variety of mouse tumor models. A potential caveat of systemic delivery of IL-27 using rAAV is that there is no practical method to terminate IL-27 production when its biological activity is no longer needed. Therefore, in this work, we tested if directly injecting AAV-IL-27 into tumors could lead to similar anti-tumor effect yet avoiding uncontrolled IL-27 production. We found that high levels of IL-27 was produced in tumors and released to peripheral blood after AAV-IL-27 intra-tumoral injection. AAV-IL-27 local therapy showed potent anti-tumor activity in mice bearing plasmacytoma J558 tumors and modest anti-tumor activity in mice bearing B16.F10 tumors. Intra-tumoral injection of AAV-IL-27 induced infiltration of immune effectors including CD8(+) T cells and NK cells into tumors, caused systemic reduction of Tregs and stimulated protective immunity. Mechanistically, we found that IL-27 induced T cell expression of CXCR3 in an IL-27R-dependent manner. Additionally, we found that AAV-IL-27 local therapy had significant synergy with anti-PD-1 or T cell adoptive transfer therapy. Importantly, in mice whose tumors were completely rejected, IL-27 serum levels were significantly reduced or diminished. Thus, intra-tumoral injection of AAV-IL-27 is a feasible approach that can be used alone and in combination with anti-PD-1 antibody or T cell adoptive transfer for the treatment of cancer. Frontiers Media S.A. 2020-03-27 /pmc/articles/PMC7118910/ /pubmed/32292786 http://dx.doi.org/10.3389/fcell.2020.00210 Text en Copyright © 2020 Hu, Ding, Zhu, Liu, Pan, Ghoshal and Bai. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Cell and Developmental Biology Hu, Aiyan Ding, Miao Zhu, Jianmin Liu, Jin-Qing Pan, Xueliang Ghoshal, Kalpana Bai, Xue-Feng Intra-Tumoral Delivery of IL-27 Using Adeno-Associated Virus Stimulates Anti-tumor Immunity and Enhances the Efficacy of Immunotherapy |
title | Intra-Tumoral Delivery of IL-27 Using Adeno-Associated Virus Stimulates Anti-tumor Immunity and Enhances the Efficacy of Immunotherapy |
title_full | Intra-Tumoral Delivery of IL-27 Using Adeno-Associated Virus Stimulates Anti-tumor Immunity and Enhances the Efficacy of Immunotherapy |
title_fullStr | Intra-Tumoral Delivery of IL-27 Using Adeno-Associated Virus Stimulates Anti-tumor Immunity and Enhances the Efficacy of Immunotherapy |
title_full_unstemmed | Intra-Tumoral Delivery of IL-27 Using Adeno-Associated Virus Stimulates Anti-tumor Immunity and Enhances the Efficacy of Immunotherapy |
title_short | Intra-Tumoral Delivery of IL-27 Using Adeno-Associated Virus Stimulates Anti-tumor Immunity and Enhances the Efficacy of Immunotherapy |
title_sort | intra-tumoral delivery of il-27 using adeno-associated virus stimulates anti-tumor immunity and enhances the efficacy of immunotherapy |
topic | Cell and Developmental Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7118910/ https://www.ncbi.nlm.nih.gov/pubmed/32292786 http://dx.doi.org/10.3389/fcell.2020.00210 |
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