Intrinsic suppression of type I interferon production underlies the therapeutic efficacy of IL-15-producing natural killer cells in B-cell acute lymphoblastic leukemia
© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ..
BACKGROUND: Type I interferons (IFN-Is), secreted by hematopoietic cells, drive immune surveillance of solid tumors. However, the mechanisms of suppression of IFN-I-driven immune responses in hematopoietic malignancies including B-cell acute lymphoblastic leukemia (B-ALL) are unknown.
METHODS: Using high-dimensional cytometry, we delineate the defects in IFN-I production and IFN-I-driven immune responses in high-grade primary human and mouse B-ALLs. We develop natural killer (NK) cells as therapies to counter the intrinsic suppression of IFN-I production in B-ALL.
RESULTS: We find that high expression of IFN-I signaling genes predicts favorable clinical outcome in patients with B-ALL, underscoring the importance of the IFN-I pathway in this malignancy. We show that human and mouse B-ALL microenvironments harbor an intrinsic defect in paracrine (plasmacytoid dendritic cell) and/or autocrine (B-cell) IFN-I production and IFN-I-driven immune responses. Reduced IFN-I production is sufficient for suppressing the immune system and promoting leukemia development in mice prone to MYC-driven B-ALL. Among anti-leukemia immune subsets, suppression of IFN-I production most markedly lowers the transcription of IL-15 and reduces NK-cell number and effector maturation in B-ALL microenvironments. Adoptive transfer of healthy NK cells significantly prolongs survival of overt ALL-bearing transgenic mice. Administration of IFN-Is to B-ALL-prone mice reduces leukemia progression and increases the frequencies of total NK and NK-cell effectors in circulation. Ex vivo treatment of malignant and non-malignant immune cells in primary mouse B-ALL microenvironments with IFN-Is fully restores proximal IFN-I signaling and partially restores IL-15 production. In B-ALL patients, the suppression of IL-15 is the most severe in difficult-to-treat subtypes with MYC overexpression. MYC overexpression promotes sensitivity of B-ALL to NK cell-mediated killing. To counter the suppressed IFN-I-induced IL-15 production in MYChigh human B-ALL, we CRISPRa-engineered a novel human NK-cell line that secretes IL-15. CRISPRa IL-15-secreting human NK cells kill high-grade human B-ALL in vitro and block leukemia progression in vivo more effectively than NK cells that do not produce IL-15.
CONCLUSION: We find that restoration of the intrinsically suppressed IFN-I production in B-ALL underlies the therapeutic efficacy of IL-15-producing NK cells and that such NK cells represent an attractive therapeutic solution for the problem of drugging MYC in high-grade B-ALL.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:11 |
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| Enthalten in: |
Journal for immunotherapy of cancer - 11(2023), 5 vom: 01. Mai |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Kumar, Anil [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 24.05.2023 Date Revised 26.06.2023 published: Print Citation Status MEDLINE |
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| doi: |
10.1136/jitc-2022-006649 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM357197127 |
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| 100 | 1 | |a Kumar, Anil |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Intrinsic suppression of type I interferon production underlies the therapeutic efficacy of IL-15-producing natural killer cells in B-cell acute lymphoblastic leukemia |
| 264 | 1 | |c 2023 | |
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| 500 | |a Date Completed 24.05.2023 | ||
| 500 | |a Date Revised 26.06.2023 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. | ||
| 520 | |a BACKGROUND: Type I interferons (IFN-Is), secreted by hematopoietic cells, drive immune surveillance of solid tumors. However, the mechanisms of suppression of IFN-I-driven immune responses in hematopoietic malignancies including B-cell acute lymphoblastic leukemia (B-ALL) are unknown | ||
| 520 | |a METHODS: Using high-dimensional cytometry, we delineate the defects in IFN-I production and IFN-I-driven immune responses in high-grade primary human and mouse B-ALLs. We develop natural killer (NK) cells as therapies to counter the intrinsic suppression of IFN-I production in B-ALL | ||
| 520 | |a RESULTS: We find that high expression of IFN-I signaling genes predicts favorable clinical outcome in patients with B-ALL, underscoring the importance of the IFN-I pathway in this malignancy. We show that human and mouse B-ALL microenvironments harbor an intrinsic defect in paracrine (plasmacytoid dendritic cell) and/or autocrine (B-cell) IFN-I production and IFN-I-driven immune responses. Reduced IFN-I production is sufficient for suppressing the immune system and promoting leukemia development in mice prone to MYC-driven B-ALL. Among anti-leukemia immune subsets, suppression of IFN-I production most markedly lowers the transcription of IL-15 and reduces NK-cell number and effector maturation in B-ALL microenvironments. Adoptive transfer of healthy NK cells significantly prolongs survival of overt ALL-bearing transgenic mice. Administration of IFN-Is to B-ALL-prone mice reduces leukemia progression and increases the frequencies of total NK and NK-cell effectors in circulation. Ex vivo treatment of malignant and non-malignant immune cells in primary mouse B-ALL microenvironments with IFN-Is fully restores proximal IFN-I signaling and partially restores IL-15 production. In B-ALL patients, the suppression of IL-15 is the most severe in difficult-to-treat subtypes with MYC overexpression. MYC overexpression promotes sensitivity of B-ALL to NK cell-mediated killing. To counter the suppressed IFN-I-induced IL-15 production in MYChigh human B-ALL, we CRISPRa-engineered a novel human NK-cell line that secretes IL-15. CRISPRa IL-15-secreting human NK cells kill high-grade human B-ALL in vitro and block leukemia progression in vivo more effectively than NK cells that do not produce IL-15 | ||
| 520 | |a CONCLUSION: We find that restoration of the intrinsically suppressed IFN-I production in B-ALL underlies the therapeutic efficacy of IL-15-producing NK cells and that such NK cells represent an attractive therapeutic solution for the problem of drugging MYC in high-grade B-ALL | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a cytokines | |
| 650 | 4 | |a hematologic neoplasms | |
| 650 | 4 | |a immune evation | |
| 650 | 4 | |a immunologic surveillance | |
| 650 | 4 | |a killer cells, natural | |
| 650 | 7 | |a Interferon-gamma |2 NLM | |
| 650 | 7 | |a 82115-62-6 |2 NLM | |
| 650 | 7 | |a Interleukin-15 |2 NLM | |
| 650 | 7 | |a Interferon Type I |2 NLM | |
| 700 | 1 | |a Taghi Khani, Adeleh |e verfasserin |4 aut | |
| 700 | 1 | |a Duault, Caroline |e verfasserin |4 aut | |
| 700 | 1 | |a Aramburo, Soraya |e verfasserin |4 aut | |
| 700 | 1 | |a Sanchez Ortiz, Ashly |e verfasserin |4 aut | |
| 700 | 1 | |a Lee, Sung June |e verfasserin |4 aut | |
| 700 | 1 | |a Chan, Anthony |e verfasserin |4 aut | |
| 700 | 1 | |a McDonald, Tinisha |e verfasserin |4 aut | |
| 700 | 1 | |a Huang, Min |e verfasserin |4 aut | |
| 700 | 1 | |a Lacayo, Norman J |e verfasserin |4 aut | |
| 700 | 1 | |a Sakamoto, Kathleen M |e verfasserin |4 aut | |
| 700 | 1 | |a Yu, Jianhua |e verfasserin |4 aut | |
| 700 | 1 | |a Hurtz, Christian |e verfasserin |4 aut | |
| 700 | 1 | |a Carroll, Martin |e verfasserin |4 aut | |
| 700 | 1 | |a Tasian, Sarah K |e verfasserin |4 aut | |
| 700 | 1 | |a Ghoda, Lucy |e verfasserin |4 aut | |
| 700 | 1 | |a Marcucci, Guido |e verfasserin |4 aut | |
| 700 | 1 | |a Gu, Zhaohui |e verfasserin |4 aut | |
| 700 | 1 | |a Rosen, Steven T |e verfasserin |4 aut | |
| 700 | 1 | |a Armenian, Saro |e verfasserin |4 aut | |
| 700 | 1 | |a Izraeli, Shai |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Chun-Wei |e verfasserin |4 aut | |
| 700 | 1 | |a Caligiuri, Michael A |e verfasserin |4 aut | |
| 700 | 1 | |a Forman, Stephen J |e verfasserin |4 aut | |
| 700 | 1 | |a Maecker, Holden T |e verfasserin |4 aut | |
| 700 | 1 | |a Swaminathan, Srividya |e verfasserin |4 aut | |
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