Overcoming cancer-associated fibroblast-induced immunosuppression by anti-interleukin-6 receptor antibody
Abstract Cancer-associated fibroblasts (CAFs) are a critical component of the tumor microenvironment and play a central role in tumor progression. Previously, we reported that CAFs might induce tumor immunosuppression via interleukin-6 (IL-6) and promote tumor progression by blocking local IL-6 in the tumor microenvironment with neutralizing antibody. Here, we explore whether an anti-IL-6 receptor antibody could be used as systemic therapy to treat cancer, and further investigate the mechanisms by which IL-6 induces tumor immunosuppression. In clinical samples, IL-6 expression was significantly correlated with α-smooth muscle actin expression, and high IL-6 cases showed tumor immunosuppression. Multivariate analysis showed that IL-6 expression was an independent prognostic factor. In vitro, IL-6 contributed to cell proliferation and differentiation into CAFs. Moreover, IL-6 increased hypoxia-inducible factor 1α (HIF1α) expression and induced tumor immunosuppression by enhancing glucose uptake by cancer cells and competing for glucose with immune cells. MR16-1, a rodent analog of anti-IL-6 receptor antibody, overcame CAF-induced immunosuppression and suppressed tumor progression in immunocompetent murine cancer models by regulating HIF1α activation in vivo. The anti-IL-6 receptor antibody could be systemically employed to overcome tumor immunosuppression and improve patient survival with various cancers. Furthermore, the tumor immunosuppression was suggested to be induced by IL-6 via HIF1α activation..
| Medienart: |
Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:72 |
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| Enthalten in: |
Cancer immunology immunotherapy - 72(2023), 7 vom: 10. Feb., Seite 2029-2044 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Nishiwaki, Noriyuki [VerfasserIn] |
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| Links: |
Volltext [lizenzpflichtig] |
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| BKL: | |
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| Themen: |
Cancer-associated fibroblasts |
| Anmerkungen: |
© The Author(s) 2023 |
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| doi: |
10.1007/s00262-023-03378-7 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
OLC2143838344 |
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| 520 | |a Abstract Cancer-associated fibroblasts (CAFs) are a critical component of the tumor microenvironment and play a central role in tumor progression. Previously, we reported that CAFs might induce tumor immunosuppression via interleukin-6 (IL-6) and promote tumor progression by blocking local IL-6 in the tumor microenvironment with neutralizing antibody. Here, we explore whether an anti-IL-6 receptor antibody could be used as systemic therapy to treat cancer, and further investigate the mechanisms by which IL-6 induces tumor immunosuppression. In clinical samples, IL-6 expression was significantly correlated with α-smooth muscle actin expression, and high IL-6 cases showed tumor immunosuppression. Multivariate analysis showed that IL-6 expression was an independent prognostic factor. In vitro, IL-6 contributed to cell proliferation and differentiation into CAFs. Moreover, IL-6 increased hypoxia-inducible factor 1α (HIF1α) expression and induced tumor immunosuppression by enhancing glucose uptake by cancer cells and competing for glucose with immune cells. MR16-1, a rodent analog of anti-IL-6 receptor antibody, overcame CAF-induced immunosuppression and suppressed tumor progression in immunocompetent murine cancer models by regulating HIF1α activation in vivo. The anti-IL-6 receptor antibody could be systemically employed to overcome tumor immunosuppression and improve patient survival with various cancers. Furthermore, the tumor immunosuppression was suggested to be induced by IL-6 via HIF1α activation. | ||
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| 650 | 4 | |a Drug repositioning | |
| 650 | 4 | |a Interleukin-6 receptor antibody | |
| 650 | 4 | |a Tumor microenvironment | |
| 700 | 1 | |a Noma, Kazuhiro |4 aut | |
| 700 | 1 | |a Ohara, Toshiaki |4 aut | |
| 700 | 1 | |a Kunitomo, Tomoyoshi |4 aut | |
| 700 | 1 | |a Kawasaki, Kento |4 aut | |
| 700 | 1 | |a Akai, Masaaki |4 aut | |
| 700 | 1 | |a Kobayashi, Teruki |4 aut | |
| 700 | 1 | |a Narusaka, Toru |4 aut | |
| 700 | 1 | |a Kashima, Hajime |4 aut | |
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| 700 | 1 | |a Komoto, Satoshi |4 aut | |
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| 700 | 1 | |a Maeda, Naoaki |4 aut | |
| 700 | 1 | |a Kikuchi, Satoru |4 aut | |
| 700 | 1 | |a Tanabe, Shunsuke |4 aut | |
| 700 | 1 | |a Tazawa, Hiroshi |4 aut | |
| 700 | 1 | |a Shirakawa, Yasuhiro |4 aut | |
| 700 | 1 | |a Fujiwara, Toshiyoshi |4 aut | |
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