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肿瘤细胞内在的 I 型 IFN 信号介导的代谢重编程是阻断 CD47-SIRPα 疗效所必需的。

Metabolic reprograming mediated by tumor cell-intrinsic type I IFN signaling is required for CD47-SIRPα blockade efficacy.

机构信息

Key Laboratory of Epigenetic Regulation and Intervention, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.

CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.

出版信息

Nat Commun. 2024 Jul 9;15(1):5759. doi: 10.1038/s41467-024-50136-z.

DOI:10.1038/s41467-024-50136-z
PMID:38982116
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11233683/
Abstract

Type I interferons have been well recognized for their roles in various types of immune cells during tumor immunotherapy. However, their direct effects on tumor cells are less understood. Oxidative phosphorylation is typically latent in tumor cells. Whether oxidative phosphorylation can be targeted for immunotherapy remains unclear. Here, we find that tumor cell responsiveness to type I, but not type II interferons, is essential for CD47-SIRPα blockade immunotherapy in female mice. Mechanistically, type I interferons directly reprogram tumor cell metabolism by activating oxidative phosphorylation for ATP production in an ISG15-dependent manner. ATP extracellular release is also promoted by type I interferons due to enhanced secretory autophagy. Functionally, tumor cells with genetic deficiency in oxidative phosphorylation or autophagy are resistant to CD47-SIRPα blockade. ATP released upon CD47-SIRPα blockade is required for antitumor T cell response induction via P2X7 receptor-mediated dendritic cell activation. Based on this mechanism, combinations with inhibitors of ATP-degrading ectoenzymes, CD39 and CD73, are designed and show synergistic antitumor effects with CD47-SIRPα blockade. Together, these data reveal an important role of type I interferons on tumor cell metabolic reprograming for tumor immunotherapy and provide rational strategies harnessing this mechanism for enhanced efficacy of CD47-SIRPα blockade.

摘要

I 型干扰素在肿瘤免疫治疗中已被广泛认可，其在各种类型免疫细胞中发挥着重要作用。然而，其对肿瘤细胞的直接作用仍知之甚少。肿瘤细胞通常潜伏着氧化磷酸化。氧化磷酸化是否可以作为免疫治疗的靶点尚不清楚。在这里，我们发现，肿瘤细胞对 I 型干扰素而非 II 型干扰素的反应性，对于 CD47-SIRPα 阻断免疫疗法在雌性小鼠中的疗效至关重要。在机制上，I 型干扰素通过依赖 ISG15 的方式直接激活氧化磷酸化，从而重新编程肿瘤细胞代谢以产生 ATP。I 型干扰素还通过增强的分泌自噬促进 ATP 的细胞外释放。从功能上讲，氧化磷酸化或自噬基因缺陷的肿瘤细胞对 CD47-SIRPα 阻断具有抗性。CD47-SIRPα 阻断后释放的 ATP 通过 P2X7 受体介导的树突状细胞激活，诱导抗肿瘤 T 细胞反应。基于这一机制，设计了与 ATP 降解胞外酶抑制剂 CD39 和 CD73 的组合，与 CD47-SIRPα 阻断具有协同的抗肿瘤作用。总之，这些数据揭示了 I 型干扰素在肿瘤细胞代谢重编程中的重要作用，为肿瘤免疫治疗提供了合理的策略，利用这一机制增强了 CD47-SIRPα 阻断的疗效。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/254c/11233683/9f12948f984e/41467_2024_50136_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/254c/11233683/0d4eb1e52534/41467_2024_50136_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/254c/11233683/00d2ff472e46/41467_2024_50136_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/254c/11233683/6da0ce04289d/41467_2024_50136_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/254c/11233683/ef4f2ced13c9/41467_2024_50136_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/254c/11233683/0262c90f12a0/41467_2024_50136_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/254c/11233683/663abca76e01/41467_2024_50136_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/254c/11233683/6078ddb6ab79/41467_2024_50136_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/254c/11233683/0a400c2faf1b/41467_2024_50136_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/254c/11233683/9f12948f984e/41467_2024_50136_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/254c/11233683/0d4eb1e52534/41467_2024_50136_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/254c/11233683/00d2ff472e46/41467_2024_50136_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/254c/11233683/6da0ce04289d/41467_2024_50136_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/254c/11233683/ef4f2ced13c9/41467_2024_50136_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/254c/11233683/0262c90f12a0/41467_2024_50136_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/254c/11233683/663abca76e01/41467_2024_50136_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/254c/11233683/6078ddb6ab79/41467_2024_50136_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/254c/11233683/0a400c2faf1b/41467_2024_50136_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/254c/11233683/9f12948f984e/41467_2024_50136_Fig9_HTML.jpg

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