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Sensitization of ovarian tumor to immune checkpoint blockade by boosting senescence-associated secretory phenotype
Therapy-induced senescence-associated secretory phenotype (SASP) correlates with overcoming resistance to immune checkpoint blockade (ICB). Intrinsic resistance to ICB is a major clinical challenge. For example, ovarian cancer is largely resistant to ICB. Here we show that adoptive transfer of SASP-...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7811168/ https://www.ncbi.nlm.nih.gov/pubmed/33490922 http://dx.doi.org/10.1016/j.isci.2020.102016 |
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author | Hao, Xue Zhao, Bo Zhou, Wei Liu, Heng Fukumoto, Takeshi Gabrilovich, Dmitry Zhang, Rugang |
author_facet | Hao, Xue Zhao, Bo Zhou, Wei Liu, Heng Fukumoto, Takeshi Gabrilovich, Dmitry Zhang, Rugang |
author_sort | Hao, Xue |
collection | PubMed |
description | Therapy-induced senescence-associated secretory phenotype (SASP) correlates with overcoming resistance to immune checkpoint blockade (ICB). Intrinsic resistance to ICB is a major clinical challenge. For example, ovarian cancer is largely resistant to ICB. Here we show that adoptive transfer of SASP-boosted ex vivo therapy-induced senescent cells sensitizes ovarian tumor to ICB. Topoisomerase 1 (TOP1) inhibitors such as irinotecan enhance cisplatin-induced SASP, which depends on the TOP1 cleavage complex-regulated cGAS pathway. Significantly, intraperitoneal transfer of cisplatin-induced, SASP-boosted senescent cells with irinotecan sensitizes ovarian tumor to anti-PD-1 antibody and improves the survival of tumor-bearing mice in an immunocompetent, syngeneic model. This correlates with the infiltration of transferred senescent cells in the established orthotopic tumors and an increase in the infiltration of activated CD8(+) T cells and dendritic cells in the tumor bed. Our findings indicate that adoptive transfer of SASP-boosted therapy-induced senescent cells represents a potential therapeutic strategy to sensitize tumors to ICB. |
format | Online Article Text |
id | pubmed-7811168 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-78111682021-01-22 Sensitization of ovarian tumor to immune checkpoint blockade by boosting senescence-associated secretory phenotype Hao, Xue Zhao, Bo Zhou, Wei Liu, Heng Fukumoto, Takeshi Gabrilovich, Dmitry Zhang, Rugang iScience Article Therapy-induced senescence-associated secretory phenotype (SASP) correlates with overcoming resistance to immune checkpoint blockade (ICB). Intrinsic resistance to ICB is a major clinical challenge. For example, ovarian cancer is largely resistant to ICB. Here we show that adoptive transfer of SASP-boosted ex vivo therapy-induced senescent cells sensitizes ovarian tumor to ICB. Topoisomerase 1 (TOP1) inhibitors such as irinotecan enhance cisplatin-induced SASP, which depends on the TOP1 cleavage complex-regulated cGAS pathway. Significantly, intraperitoneal transfer of cisplatin-induced, SASP-boosted senescent cells with irinotecan sensitizes ovarian tumor to anti-PD-1 antibody and improves the survival of tumor-bearing mice in an immunocompetent, syngeneic model. This correlates with the infiltration of transferred senescent cells in the established orthotopic tumors and an increase in the infiltration of activated CD8(+) T cells and dendritic cells in the tumor bed. Our findings indicate that adoptive transfer of SASP-boosted therapy-induced senescent cells represents a potential therapeutic strategy to sensitize tumors to ICB. Elsevier 2020-12-30 /pmc/articles/PMC7811168/ /pubmed/33490922 http://dx.doi.org/10.1016/j.isci.2020.102016 Text en © 2020 The Author(s) http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Article Hao, Xue Zhao, Bo Zhou, Wei Liu, Heng Fukumoto, Takeshi Gabrilovich, Dmitry Zhang, Rugang Sensitization of ovarian tumor to immune checkpoint blockade by boosting senescence-associated secretory phenotype |
title | Sensitization of ovarian tumor to immune checkpoint blockade by boosting senescence-associated secretory phenotype |
title_full | Sensitization of ovarian tumor to immune checkpoint blockade by boosting senescence-associated secretory phenotype |
title_fullStr | Sensitization of ovarian tumor to immune checkpoint blockade by boosting senescence-associated secretory phenotype |
title_full_unstemmed | Sensitization of ovarian tumor to immune checkpoint blockade by boosting senescence-associated secretory phenotype |
title_short | Sensitization of ovarian tumor to immune checkpoint blockade by boosting senescence-associated secretory phenotype |
title_sort | sensitization of ovarian tumor to immune checkpoint blockade by boosting senescence-associated secretory phenotype |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7811168/ https://www.ncbi.nlm.nih.gov/pubmed/33490922 http://dx.doi.org/10.1016/j.isci.2020.102016 |
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