論文 - 詳細
| RRC ID | 78775 |
|---|---|
| 著者 | Bao Y, Qiao Y, Choi JE, Zhang Y, Mannan R, Cheng C, He T, Zheng Y, Yu J, Gondal M, Cruz G, Grove S, Cao X, Su F, Wang R, Chang Y, Kryczek I, Cieslik M, Green MD, Zou W, Chinnaiyan AM. |
| タイトル | Targeting the lipid kinase PIKfyve upregulates surface expression of MHC class I to augment cancer immunotherapy. |
| ジャーナル | Proc Natl Acad Sci U S A |
| Abstract |
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. |
| 巻・号 | 120(49) |
| ページ | e2314416120 |
| 公開日 | 2023-12-5 |
| DOI | 10.1073/pnas.2314416120 |
| PMID | 38011559 |
| PMC | PMC10710078 |
| MeSH | Animals CD8-Positive T-Lymphocytes* Genes, MHC Class I Histocompatibility Antigens Class I Humans Immunotherapy / methods Lipids Mice Neoplasms* / genetics Neoplasms* / therapy |
| IF | 9.412 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 2 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | B16/BL6(RCB2638) |