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Nano Research 2023, 16(12): 13250-13258 https://doi.org/10.1007/s12274-023-5581-6
Research Article | Issue | Published: 18 March 2023

Immunogenic cell death effects induced by doxorubicin improved chemo-immunotherapy via restoration of granzyme B activity

Show Author's Information Tao Huang1,§,  Xiaofan Sun1,§,  Yingqiu Qi1,2,§,  Xi Yang1,  Linyao Fan1,  Mengdie Chen2,  Yale Yue2,  Hong Ge3,  Yiye Li4,  Guangjun Nie4( ),  Huan Min1,2( ),  Xianfu Sun1( )
Department of Breast Disease, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Henan Institute of Advanced Technology, Zhengzhou University, Zhengzhou 450008, China
Department of Pharmacology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China
Department of Radiation Oncology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450003, China
CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety & CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing 100190, China

§ Tao Huang, Xiaofan Sun, and Yingqiu Qi contributed equally to this work.

Keywords:
nanomedicine, chemo-immunotherapy, immunogenic cell death, granzyme B, serpinb9
Topics:
Immunology
Cite this article:
Huang T, Sun X, Qi Y, et al. Immunogenic cell death effects induced by doxorubicin improved chemo-immunotherapy via restoration of granzyme B activity. Nano Research, 2023, 16(12): 13250-13258. https://doi.org/10.1007/s12274-023-5581-6
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Abstract Full text Electronic supplementary material About this article

Chemotherapy remains one of the irreplaceable treatments for cancer therapy. The use of immunogenic cell death (ICD)-inducing chemotherapeutic drugs offers a practical strategy for killing cancer cells, simultaneously eliciting an antitumor immune response by promoting the recruitment of cytotoxic immune cells and production of granzyme B (GrB). However, numerous malignant cancers adaptively acquired the capacity of secreting serpinb9 (Sb9), a physiological inhibitor of GrB, which can reversibly inhibit the biological activity of GrB. To circumvent this dilemma, in this study, an integrated tailor-made nanomedicine composed of tumor-targeting peptide (Arg-Gly-Asp, RGD) decorated liposome, doxorubicin (DOX, an effective ICD inducer), and the compound 3034 (an inhibitor of Sb9), is developed (termed as D3RL) for breast cancer chemo-immunotherapy. In vitro and in vivo studies show that D3RL can directly kill tumor cells and trigger the host immune response by inducing ICD. Meanwhile, D3RL can competitively relieve the inhibition of Sb9 to GrB. The restored GrB can not only effectively induce tumor immunotherapy, but also degrade matrix components in the tumor microenvironment, consequently improving the infiltration of immune cells and the penetration of nanomedicines, which in return enhance the combined antitumor effect. Taken together, this work develops an integrated therapeutic solution for targeted production and restoration of GrB to achieve a combined chemo-immunotherapy for breast cancer.


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Abstract
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Electronic supplementary material
About this article

Immunogenic cell death effects induced by doxorubicin improved chemo-immunotherapy via restoration of granzyme B activity

Show Author's information Tao Huang1,§, Xiaofan Sun1,§, Yingqiu Qi1,2,§, Xi Yang1, Linyao Fan1, Mengdie Chen2, Yale Yue2, Hong Ge3, Yiye Li4, Guangjun Nie4( ), Huan Min1,2( ), Xianfu Sun1( )
Department of Breast Disease, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Henan Institute of Advanced Technology, Zhengzhou University, Zhengzhou 450008, China
Department of Pharmacology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China
Department of Radiation Oncology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450003, China
CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety & CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing 100190, China

§ Tao Huang, Xiaofan Sun, and Yingqiu Qi contributed equally to this work.

Abstract

Chemotherapy remains one of the irreplaceable treatments for cancer therapy. The use of immunogenic cell death (ICD)-inducing chemotherapeutic drugs offers a practical strategy for killing cancer cells, simultaneously eliciting an antitumor immune response by promoting the recruitment of cytotoxic immune cells and production of granzyme B (GrB). However, numerous malignant cancers adaptively acquired the capacity of secreting serpinb9 (Sb9), a physiological inhibitor of GrB, which can reversibly inhibit the biological activity of GrB. To circumvent this dilemma, in this study, an integrated tailor-made nanomedicine composed of tumor-targeting peptide (Arg-Gly-Asp, RGD) decorated liposome, doxorubicin (DOX, an effective ICD inducer), and the compound 3034 (an inhibitor of Sb9), is developed (termed as D3RL) for breast cancer chemo-immunotherapy. In vitro and in vivo studies show that D3RL can directly kill tumor cells and trigger the host immune response by inducing ICD. Meanwhile, D3RL can competitively relieve the inhibition of Sb9 to GrB. The restored GrB can not only effectively induce tumor immunotherapy, but also degrade matrix components in the tumor microenvironment, consequently improving the infiltration of immune cells and the penetration of nanomedicines, which in return enhance the combined antitumor effect. Taken together, this work develops an integrated therapeutic solution for targeted production and restoration of GrB to achieve a combined chemo-immunotherapy for breast cancer.

Keywords: nanomedicine, chemo-immunotherapy, immunogenic cell death, granzyme B, serpinb9

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Publication history
Copyright
Acknowledgements

Publication history

Received: 10 January 2023
Revised: 14 February 2023
Accepted: 14 February 2023
Published: 18 March 2023
Issue date: December 2023

Copyright

© Tsinghua University Press 2023

Acknowledgements

The authors thank Prof. Fazhan Wang (the First Affiliated Hospital, Zhengzhou University) and Prof. Bing Jiang (Nanozyme Medical Center, Zhengzhou University) for assistance with the histological examination and bioimaging in vivo and ex vivo. The authors also thank the center of Advanced Analysis & Gene Sequencing, Zhengzhou University for technical assistance. This work was supported by grants from the National Natural Science Foundation of China (Nos. 32000998, and 32201240). The Young Elite Scientists Sponsorship Program by Henan Association for Science and Technology (No. 2022HYTP046), the China Postdoctoral Science Foundation (Nos. 2019TQ0285, 2019M662513, and 2021TQ0298), Henan provincial Medical Science and Technology Research Project (No. LHGJ20210210), and Science and Technology Development Project of Henan Province (Nos. 212102310138 and 222102310525).

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