Macrophages reprogramming improves immunotherapy of IL-33 in peritoneal metastasis of gastric cancer
Abstract Peritoneal metastasis (PM) has a suppressive tumor immune microenvironment (TIME) that limits the effects of immunotherapy. This study aimed to investigate the immunomodulatory effects of intraperitoneal administration of IL-33, a cytokine that is reported to potentiate antitumor immunity and inhibit metastasis. We found survival was significantly prolonged in patients with high IL-33 mRNA expression. In immunocompetent mice, intraperitoneal administration of IL-33 could induce a celiac inflammatory environment, activate immunologic effector cells, and reverse the immunosuppressive tumor microenvironment, which effectively delayed tumor progression and PM of gastric cancer. Mechanistically, IL-33 could induce M2 polarization by activating p38-GATA-binding protein 3 signaling. IL-33 combined with anti-CSF1R or p38 inhibitor to regulate tumor-associated macrophages (TAMs) had a synergistic antitumor effect. Inducing a local inflammatory milieu by IL-33 administration provided a novel approach for treating peritoneal metastasis, which, when combined with TAM reprogramming to reshape TIME, can achieve better treatment efficacy..
Synopsis The suppressive tumor immune microenvironment limits the effectiveness of immunotherapy for peritoneal metastasis. Because of its known role in antitumor immunity, local administration of IL-33 was tested as a potential therapy in immunocompetent mice. In human gastric cancer patients, high IL-33 mRNA expression is associated with longer overall and progression-free survival times and was associated with activation of the tumor immune microenvironment.Local delivery of IL-33 to mice challenged with mouse forestomach carcinoma cells decreased metastasis.IL-33 promoted the infiltration and activation of peritoneal immunocytes, and macrophages, and induced local inflammatory milieu in mice.IL-33 activated the p38-GATA3 signaling pathway to induce M2 polarization of macrophages.A combination of IL-33 and anti-CSF1R or p38 inhibitor synergistically inhibited tumor growth and metastasis..
The suppressive tumor immune microenvironment limits the effectiveness of immunotherapy for peritoneal metastasis. Because of its known role in antitumor immunity, local administration of IL-33 was tested as a potential therapy in immunocompetent mice..
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:16 |
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| Enthalten in: |
EMBO Molecular Medicine - 16(2024), 2 vom: 18. Jan., Seite 251-266 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Che, Keying [VerfasserIn] |
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| Links: |
Volltext [kostenfrei] |
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| Themen: |
Gastric Cancer |
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| Anmerkungen: |
© The Author(s) 2024 |
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| doi: |
10.1038/s44321-023-00012-y |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 520 | |a Abstract Peritoneal metastasis (PM) has a suppressive tumor immune microenvironment (TIME) that limits the effects of immunotherapy. This study aimed to investigate the immunomodulatory effects of intraperitoneal administration of IL-33, a cytokine that is reported to potentiate antitumor immunity and inhibit metastasis. We found survival was significantly prolonged in patients with high IL-33 mRNA expression. In immunocompetent mice, intraperitoneal administration of IL-33 could induce a celiac inflammatory environment, activate immunologic effector cells, and reverse the immunosuppressive tumor microenvironment, which effectively delayed tumor progression and PM of gastric cancer. Mechanistically, IL-33 could induce M2 polarization by activating p38-GATA-binding protein 3 signaling. IL-33 combined with anti-CSF1R or p38 inhibitor to regulate tumor-associated macrophages (TAMs) had a synergistic antitumor effect. Inducing a local inflammatory milieu by IL-33 administration provided a novel approach for treating peritoneal metastasis, which, when combined with TAM reprogramming to reshape TIME, can achieve better treatment efficacy. | ||
| 520 | |a Synopsis The suppressive tumor immune microenvironment limits the effectiveness of immunotherapy for peritoneal metastasis. Because of its known role in antitumor immunity, local administration of IL-33 was tested as a potential therapy in immunocompetent mice. In human gastric cancer patients, high IL-33 mRNA expression is associated with longer overall and progression-free survival times and was associated with activation of the tumor immune microenvironment.Local delivery of IL-33 to mice challenged with mouse forestomach carcinoma cells decreased metastasis.IL-33 promoted the infiltration and activation of peritoneal immunocytes, and macrophages, and induced local inflammatory milieu in mice.IL-33 activated the p38-GATA3 signaling pathway to induce M2 polarization of macrophages.A combination of IL-33 and anti-CSF1R or p38 inhibitor synergistically inhibited tumor growth and metastasis. | ||
| 520 | |a The suppressive tumor immune microenvironment limits the effectiveness of immunotherapy for peritoneal metastasis. Because of its known role in antitumor immunity, local administration of IL-33 was tested as a potential therapy in immunocompetent mice. | ||
| 650 | 4 | |a IL-33 |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Gastric Cancer |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Peritoneal Metastasis |7 (dpeaa)DE-He213 | |
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| 650 | 4 | |a Tumor-associated Macrophages |7 (dpeaa)DE-He213 | |
| 700 | 1 | |a Luo, Yuting |4 aut | |
| 700 | 1 | |a Song, Xueru |4 aut | |
| 700 | 1 | |a Yang, Zhe |4 aut | |
| 700 | 1 | |a Wang, Hanbing |4 aut | |
| 700 | 1 | |a Shi, Tao |0 (orcid)0000-0002-9825-3983 |4 aut | |
| 700 | 1 | |a Wang, Yue |4 aut | |
| 700 | 1 | |a Wang, Xuan |4 aut | |
| 700 | 1 | |a Wu, Hongyan |4 aut | |
| 700 | 1 | |a Yu, Lixia |4 aut | |
| 700 | 1 | |a Liu, Baorui |4 aut | |
| 700 | 1 | |a Wei, Jia |0 (orcid)0000-0003-3024-8878 |4 aut | |
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