TY - JOUR
T1 - Targeting IFNα to tumor by anti-PD-L1 creates feedforward antitumor responses to overcome checkpoint blockade resistance
AU - Liang, Yong
AU - Tang, Haidong
AU - Guo, Jingya
AU - Qiu, Xiangyan
AU - Yang, Zecheng
AU - Ren, Zhenhua
AU - Sun, Zhichen
AU - Bian, Yingjie
AU - Xu, Lily
AU - Xu, Hairong
AU - Shen, Jiao
AU - Han, Yanfei
AU - Dong, Haidong
AU - Peng, Hua
AU - Fu, Yang-Xin
N1 - Funding Information:
We are grateful to Dr. Mingzhao Zhu for helpful suggestions and comments on the project. We thank Daryl Harmon for excellent editing. We thank Shuo Guo, Hui Su and Junfeng Hao for technical assistance, and Yuanyuan Chen and Zhenwei Yang for technician help with BLI experiments in IBP. This work was in part supported by the Cancer Prevention and Research Institute of Texas to Y.X.F., We appreciate the funding from Chinese Academy of Sciences (XDA12020212) and National Key R&D Program of China (2016YFC1303405) to H. Peng, and China Postdoctoral Science Foundation (No. 2016M600139) to Y. Liang.
Publisher Copyright:
© 2018, The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - Many patients remain unresponsive to intensive PD-1/PD-L1 blockade therapy despite the presence of tumor-infiltrating lymphocytes. We propose that impaired innate sensing might limit the complete activation of tumor-specific T cells after PD-1/PD-L1 blockade. Local delivery of type I interferons (IFNs) restores antigen presentation, but upregulates PD-L1, dampening subsequent T-cell activation. Therefore, we armed anti-PD-L1 antibody with IFNα (IFNα-anti-PD-L1) to create feedforward responses. Here, we find that a synergistic effect is achieved to overcome both type I IFN and checkpoint blockade therapy resistance with the least side effects in advanced tumors. Intriguingly, PD-L1 expressed in either tumor cells or tumor-associated host cells is sufficient for fusion protein targeting. IFNα-anti-PD-L1 activates IFNAR signaling in host cells, but not in tumor cells to initiate T-cell reactivation. Our data suggest that a next-generation PD-L1 antibody armed with IFNα improves tumor targeting and antigen presentation, while countering innate or T-cell-driven PD-L1 upregulation within tumor.
AB - Many patients remain unresponsive to intensive PD-1/PD-L1 blockade therapy despite the presence of tumor-infiltrating lymphocytes. We propose that impaired innate sensing might limit the complete activation of tumor-specific T cells after PD-1/PD-L1 blockade. Local delivery of type I interferons (IFNs) restores antigen presentation, but upregulates PD-L1, dampening subsequent T-cell activation. Therefore, we armed anti-PD-L1 antibody with IFNα (IFNα-anti-PD-L1) to create feedforward responses. Here, we find that a synergistic effect is achieved to overcome both type I IFN and checkpoint blockade therapy resistance with the least side effects in advanced tumors. Intriguingly, PD-L1 expressed in either tumor cells or tumor-associated host cells is sufficient for fusion protein targeting. IFNα-anti-PD-L1 activates IFNAR signaling in host cells, but not in tumor cells to initiate T-cell reactivation. Our data suggest that a next-generation PD-L1 antibody armed with IFNα improves tumor targeting and antigen presentation, while countering innate or T-cell-driven PD-L1 upregulation within tumor.
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U2 - 10.1038/s41467-018-06890-y
DO - 10.1038/s41467-018-06890-y
M3 - Article
C2 - 30389912
AN - SCOPUS:85056002307
SN - 2041-1723
VL - 9
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 4586
ER -