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T lymphocyte membrane-decorated epigenetic nanoinducer of interferons for cancer immunotherapy

Nature Nanotechnology volume 16, pages 1271–1280 (2021)Cite this article

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Abstract

Impaired type I interferons (IFNs) may cause immune deficiency in tumours. Current supplementary IFN therapy partially restores anticancer immunity but simultaneously induces immune evasion by upregulating multiple immune checkpoints. Here we create a T lymphocyte membrane-decorated epigenetic nanoinducer that is engineered with programmed cell death protein 1 (PD1), which we call OPEN, for the delivery of the IFN inducer ORY-1001. OPEN increases IFNs and blocks IFN-induced immune checkpoint upregulation. OPEN also targets tumours that express programmed cell death ligand 1 (PDL1) through PDL1/PD1 recognition and subsequently triggers the internalization of OPEN and immune checkpoint proteins. OPEN, which is loaded with ORY-1001, upregulates intratumoural IFNs and downstream major histocompatibility complex I and PDL1. The replenished PDL1 enables further ligation of OPEN, which in turn blocks PDL1. These sequential processes result in an eight- and 29-fold increase of the intratumoural densities of total and active cytotoxic T lymphocytes, respectively, and a strong inhibition of xenograft tumour growth. This T lymphocyte membrane-decorated epigenetic nanoinducer presents a generalizable platform to boost antitumour immunity.

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Fig. 1: Schematic illustration of the preparation and mechanism of action of OPEN.
Fig. 2: Association between intratumoural IFN signature and survival in TNBC patients and the effects of direct or ORY-1001-induced IFN supplement therapy on the survival and tumour infiltration of immune cells in murine TNBC model mice.
Fig. 3: Preparation and characterization of OPEN and its interaction with 4T1 cells.
Fig. 4: Accumulation of OPEN in the tumours.
Fig. 5: Amplifiable effects of OPEN in inducing intratumoural IFN-α/β and initiating the immune response.
Fig. 6: Effect of OPEN on CTLs and its therapeutic efficacy.

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Data availability

Source data are provided with this paper. Gene expression and survival data of TNBC patients in Fig. 2a were acquired from the cBioPortal database (www.cbioportal.org). The raw data used in Fig. 2g and Supplementary Fig. 2 are available at https://www.biosino.org/node with the dataset identifier number OEX010736. Any additional data that support the findings of this study are available from the corresponding authors upon reasonable request.

Code availability

All custom R scripts associated with this manuscript are deposited in the publicly available repository (https://gitee.com/ginwang/simm.git).

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Acknowledgements

Y.L. thanks the National Natural Science Foundation of China (81690265) for financial support. P.Z. thanks the National Natural Science Foundation of China (31870995 and 81671808), the Youth Innovation Promotion Association of CAS (2017335) and the SA-SIBS Scholarship Program for financial support. Y.L. thanks the Shandong Provincial Natural Science Foundation (ZR2019ZD25) for financial support. We are grateful to the National Centre for Protein Science Shanghai (electron microscopy system) for instrument support and technical assistance during data collection. We also thank L. Deng at the Shanghai Institute of Immunology for the kind gift of OT I mice and we thank J. Wang at Shanghai Institute of Materia Medica for the help with linker synthesis.

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Author notes

  1. These authors contributed equally: Yihui Zhai, Jinming Wang.

Authors and Affiliations

  1. State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China

    Yihui Zhai, Tianqun Lang, Ying Cai, Wei Ran, Fengqin Xiong, Chao Zheng, Pengcheng Zhang & Yaping Li

  2. University of Chinese Academy of Sciences, Beijing, China

    Yihui Zhai, Tianqun Lang, Ying Cai, Wei Ran, Pengcheng Zhang & Yaping Li

  3. State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Stem Cell Research Center, Department of Urology, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China

    Jinming Wang & Helen H. Zhu

  4. Yantai Key Laboratory of Nanomedicine & Advanced Preparations, Yantai Institute of Materia Medica, Shandong, China

    Ying Kong, Rong Rong & Pengcheng Zhang

  5. China State Institute of Pharmaceutical Industry, Shanghai, China

    Fengqin Xiong & Chao Zheng

  6. National Facility for Protein Science in Shanghai, Zhangjiang Lab, Shanghai, China

    Yanke Wang & Yang Yu

  7. Bohai Rim Advanced Research Institute for Drug Discovery, Shandong, China

    Yaping Li

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Contributions

P.Z. and Y.Z. conceived and designed the project; Y.Z. synthesized and characterized the nanovesicles; Y.Z., J.W., T.L., Y.K., R.R., Y.C., W.R., F.X., C.Z., Y.W. and Y.Y. performed the cell and animal experiments; J.W., H.H.Z. and P.Z. performed bioinformatic analysis; P.Z., Y.Z. and Y.L. interpreted the data and wrote the manuscript with input from all of the authors. P.Z. and Y.L. supervised the study.

Corresponding authors

Correspondence to Pengcheng Zhang or Yaping Li.

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Peer review information Nature Nanotechnology thanks Riccardo Dolcetti, Liangfang Zhang and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Zhai, Y., Wang, J., Lang, T. et al. T lymphocyte membrane-decorated epigenetic nanoinducer of interferons for cancer immunotherapy. Nat. Nanotechnol. 16, 1271–1280 (2021). https://doi.org/10.1038/s41565-021-00972-7

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