TY - JOUR
T1 - Next generation of tumor-activating type I IFN enhances anti-tumor immune responses to overcome therapy resistance
AU - Cao, Xuezhi
AU - Liang, Yong
AU - Hu, Zhenxiang
AU - Li, Huiyu
AU - Yang, Jiaming
AU - Hsu, Eric J.
AU - Zhu, Jiankun
AU - Zhou, Jin
AU - Fu, Yang Xin
N1 - Funding Information:
We thank the Institutional Animal Care and Use Committee Animal Resources Center and Animal Research Center. Y.-X.F. holds the Mary Nell and Ralph B. Rogers Professorship in Immunology and CPRIT Scholar in Cancer Research. This work was supported by Cancer Prevention and Research Institute of Texas (CPRIT) grants RR150072 and RP180725 given to Y.-X.F. We thank Dr. Zhijian J. Chen for providing RAW-Lucia ISG cells. We thank Anli Zhang, Benjamin Moon, Casey Moore, Changzheng Lu, Chuanhui Han, Chunbo Dong, Jian Qiao, Joonbeom Bae, Longchao Liu, Zhenhua Ren, and Zhida Liu for providing experiment materials and helpful discussions.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12/1
Y1 - 2021/12/1
N2 - Type I interferon is promising in treating different kinds of tumors, but has been limited by its toxicity, lack of tumor targeting, and very short half-life. To target tumors, reduce systemic toxicity, and increase half-life, here we engineer a masked type I IFN-Fc (ProIFN) with its natural receptor connected by a cleavable linker that can be targeted by tumor-associated proteases. ProIFN has a prolonged serum half-life and shows an improved tumor-targeting effect. Interestingly, ProIFN-treated mice show enhanced DC cross-priming and significant increased CD8+ infiltration and effector function in the tumor microenvironment. ProIFN is able to improve checkpoint blockade efficacy in established tumors, as well as radiation efficacy for both primary and metastatic tumors. ProIFN exhibits superior long-term pharmacokinetics with minimal toxicity in monkeys. Therefore, this study demonstrates an effective tumor-activating IFN that can increase targeted immunity against primary tumor or metastasis and reduce periphery toxicity to the host.
AB - Type I interferon is promising in treating different kinds of tumors, but has been limited by its toxicity, lack of tumor targeting, and very short half-life. To target tumors, reduce systemic toxicity, and increase half-life, here we engineer a masked type I IFN-Fc (ProIFN) with its natural receptor connected by a cleavable linker that can be targeted by tumor-associated proteases. ProIFN has a prolonged serum half-life and shows an improved tumor-targeting effect. Interestingly, ProIFN-treated mice show enhanced DC cross-priming and significant increased CD8+ infiltration and effector function in the tumor microenvironment. ProIFN is able to improve checkpoint blockade efficacy in established tumors, as well as radiation efficacy for both primary and metastatic tumors. ProIFN exhibits superior long-term pharmacokinetics with minimal toxicity in monkeys. Therefore, this study demonstrates an effective tumor-activating IFN that can increase targeted immunity against primary tumor or metastasis and reduce periphery toxicity to the host.
UR - http://www.scopus.com/inward/record.url?scp=85116831247&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85116831247&partnerID=8YFLogxK
U2 - 10.1038/s41467-021-26112-2
DO - 10.1038/s41467-021-26112-2
M3 - Article
C2 - 34620867
AN - SCOPUS:85116831247
SN - 2041-1723
VL - 12
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 5866
ER -