Targeting the lipid kinase PIKfyve upregulates surface expression of MHC class I to augment cancer immunotherapy
Despite the remarkable clinical success of immunotherapies in a subset of cancer patients, many fail to respond to treatment and exhibit resistance. Here, we found that genetic or pharmacologic inhibition of the lipid kinase PIKfyve, a regulator of autophagic flux and lysosomal biogenesis, upregulated surface expression of major histocompatibility complex class I (MHC-I) in cancer cells via impairing autophagic flux, resulting in enhanced cancer cell killing mediated by CD8+ T cells. Genetic depletion or pharmacologic inhibition of PIKfyve elevated tumor-specific MHC-I surface expression, increased intratumoral functional CD8+ T cells, and slowed tumor progression in multiple syngeneic mouse models. Importantly, enhanced antitumor responses by Pikfyve-depletion were CD8+ T cell- and MHC-I-dependent, as CD8+ T cell depletion or B2m knockout rescued tumor growth. Furthermore, PIKfyve inhibition improved response to immune checkpoint blockade (ICB), adoptive cell therapy, and a therapeutic vaccine. High expression of PIKFYVE was also predictive of poor response to ICB and prognostic of poor survival in ICB-treated cohorts. Collectively, our findings show that targeting PIKfyve enhances immunotherapies by elevating surface expression of MHC-I in cancer cells, and PIKfyve inhibitors have potential as agents to increase immunotherapy response in cancer patients.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:120 |
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| Enthalten in: |
Proceedings of the National Academy of Sciences of the United States of America - 120(2023), 49 vom: 05. Dez., Seite e2314416120 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Bao, Yi [VerfasserIn] |
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| Links: |
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| Themen: |
Cancer |
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| Anmerkungen: |
Date Completed 29.11.2023 Date Revised 02.03.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1073/pnas.2314416120 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 520 | |a Despite the remarkable clinical success of immunotherapies in a subset of cancer patients, many fail to respond to treatment and exhibit resistance. Here, we found that genetic or pharmacologic inhibition of the lipid kinase PIKfyve, a regulator of autophagic flux and lysosomal biogenesis, upregulated surface expression of major histocompatibility complex class I (MHC-I) in cancer cells via impairing autophagic flux, resulting in enhanced cancer cell killing mediated by CD8+ T cells. Genetic depletion or pharmacologic inhibition of PIKfyve elevated tumor-specific MHC-I surface expression, increased intratumoral functional CD8+ T cells, and slowed tumor progression in multiple syngeneic mouse models. Importantly, enhanced antitumor responses by Pikfyve-depletion were CD8+ T cell- and MHC-I-dependent, as CD8+ T cell depletion or B2m knockout rescued tumor growth. Furthermore, PIKfyve inhibition improved response to immune checkpoint blockade (ICB), adoptive cell therapy, and a therapeutic vaccine. High expression of PIKFYVE was also predictive of poor response to ICB and prognostic of poor survival in ICB-treated cohorts. Collectively, our findings show that targeting PIKfyve enhances immunotherapies by elevating surface expression of MHC-I in cancer cells, and PIKfyve inhibitors have potential as agents to increase immunotherapy response in cancer patients | ||
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| 700 | 1 | |a Qiao, Yuanyuan |e verfasserin |4 aut | |
| 700 | 1 | |a Choi, Jae Eun |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Yuping |e verfasserin |4 aut | |
| 700 | 1 | |a Mannan, Rahul |e verfasserin |4 aut | |
| 700 | 1 | |a Cheng, Caleb |e verfasserin |4 aut | |
| 700 | 1 | |a He, Tongchen |e verfasserin |4 aut | |
| 700 | 1 | |a Zheng, Yang |e verfasserin |4 aut | |
| 700 | 1 | |a Yu, Jiali |e verfasserin |4 aut | |
| 700 | 1 | |a Gondal, Mahnoor |e verfasserin |4 aut | |
| 700 | 1 | |a Cruz, Gabriel |e verfasserin |4 aut | |
| 700 | 1 | |a Grove, Sara |e verfasserin |4 aut | |
| 700 | 1 | |a Cao, Xuhong |e verfasserin |4 aut | |
| 700 | 1 | |a Su, Fengyun |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Rui |e verfasserin |4 aut | |
| 700 | 1 | |a Chang, Yu |e verfasserin |4 aut | |
| 700 | 1 | |a Kryczek, Ilona |e verfasserin |4 aut | |
| 700 | 1 | |a Cieslik, Marcin |e verfasserin |4 aut | |
| 700 | 1 | |a Green, Michael D |e verfasserin |4 aut | |
| 700 | 1 | |a Zou, Weiping |e verfasserin |4 aut | |
| 700 | 1 | |a Chinnaiyan, Arul M |e verfasserin |4 aut | |
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