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Nanocages displaying SIRP gamma clusters combined with prophagocytic stimulus of phagocytes potentiate anti-tumor immunity

Cancer Gene Therapy volume 28, pages 960–970 (2021)Cite this article

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Abstract

Antigen-presenting cells (APCs), including macrophages and dendritic cells (DCs), play a crucial role in bridging innate and adaptive immunity; thereby, innate immune checkpoint blockade-based therapy is an attractive approach for the induction of sustainable tumor-specific immunity. The interaction between the cluster of differentiation 47 (CD47) on tumor and signal-regulatory protein alpha (SIRPα) on phagocytic cells inhibits the phagocytic function of APCs, acting as a “don’t eat me” signal. Accordingly, CD47 blockade is known to increase tumor cell phagocytosis, eliciting tumor-specific CD8+ T-cell immunity. Here, we introduced a nature-derived nanocage to deliver SIRPγ for blocking of antiphagocytic signaling through binding to CD47 and combined it with prophagocytic stimuli using a metabolic reprogramming reagent for APCs (CpG-oligodeoxynucleotides). Upon delivering the clustered SIRPγ variant, the nanocage showed enhanced CD47 binding profiles on tumor cells, thereby promoting active engulfment by phagocytes. Moreover, combination with CpG potentiated the prophagocytic ability, leading to the establishment of antitumorigenic surroundings. This combination treatment could competently inhibit tumor growth by invigorating APCs and CD8+ T-cells in TMEs in B16F10 orthotopic tumor models, known to be resistant to CD47-targeting therapeutics. Collectively, enhanced delivery of an innate immune checkpoint antagonist with metabolic modulation stimuli of immune cells could be a promising strategy for arousing immune responses against cancer.

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Fig. 1: FSγ biosynthesizes into a nanosized globular molecule by the E.coli expression system.
Fig. 2: FSγ can antagonize CD47 of cancer cells and enhance the phagocytic activity of APCs in vitro by blocking the CD47-SIRPα axis.
Fig. 3: Treatment with FSγV could form efficient antitumor immunity in vivo.
Fig. 4: FSγV-treatment with CpG could enhance phagocytosis of APCs in vitro.
Fig. 5: Combination treatment with CpG and FSγV could reinforce antitumor immunity in vivo.
Fig. 6: FSγV and CpG potentiate antitumor immunity through efficient cancer cells engulfment by phagocytes.

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Acknowledgements

Y.C. and G.-H.N. contributed equally to this work. E.J.L. and I.-S.K. contributed equally to this work as corresponding authors.

Funding

This work was supported by grants from the National Research Foundation of Korea (NRF) funded by the Korean government (2017R1A3B1023418, 2018H1A2A1063186, and 2021R1C1C1008217), KU-KIST Graduate School of Converging Science and Technology Program, and KIST Institutional Program.

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  1. These authors contributed equally: Yoonjeong Choi, Gi-Hoon Nam.

Authors and Affiliations

  1. KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, Republic of Korea

    Yoonjeong Choi, Gi Beom Kim, Seohyun Kim, Yoon Kyoung Kim, Seong A. Kim & In-San Kim

  2. Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Seoul, Republic of Korea

    Yoonjeong Choi, Gi-Hoon Nam, Gi Beom Kim, Seohyun Kim, Yoon Kyoung Kim, Seong A. Kim & In-San Kim

  3. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA

    Gi-Hoon Nam

  4. Department of Physiology, School of Medicine, Kyungpook National University, Daegu, Republic of Korea

    Ha-Jeong Kim

  5. Department of Chemical Engineering, School of Applied Chemical Engineering, Kyungpook National University, Daegu, Republic of Korea

    Eun Jung Lee

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Choi, Y., Nam, GH., Kim, G.B. et al. Nanocages displaying SIRP gamma clusters combined with prophagocytic stimulus of phagocytes potentiate anti-tumor immunity. Cancer Gene Ther 28, 960–970 (2021). https://doi.org/10.1038/s41417-021-00372-y

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