Targeting IFNα to tumor by anti-PD-L1 creates feedforward antitumor responses to overcome checkpoint blockade resistance

Yong Liang, Haidong Tang (), Jingya Guo, Xiangyan Qiu, Zecheng Yang, Zhenhua Ren, Zhichen Sun, Yingjie Bian, Lily Xu, Hairong Xu, Jiao Shen, Yanfei Han, Haidong Dong, Hua Peng () and Yang-Xin Fu ()
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Yong Liang: Institute of Biophysics, Chinese Academy of Sciences
Haidong Tang: Tsinghua University
Jingya Guo: Institute of Biophysics, Chinese Academy of Sciences
Xiangyan Qiu: University of Texas Southwestern Medical Center
Zecheng Yang: University of Chinese Academy of Sciences
Zhenhua Ren: University of Texas Southwestern Medical Center
Zhichen Sun: Institute of Biophysics, Chinese Academy of Sciences
Yingjie Bian: Institute of Biophysics, Chinese Academy of Sciences
Lily Xu: Wellesley College
Hairong Xu: Institute of Biophysics, Chinese Academy of Sciences
Jiao Shen: University of Chinese Academy of Sciences
Yanfei Han: Institute of Biophysics, Chinese Academy of Sciences
Haidong Dong: College of Medicine, Mayo Clinic
Hua Peng: Institute of Biophysics, Chinese Academy of Sciences
Yang-Xin Fu: University of Texas Southwestern Medical Center

Nature Communications, 2018, vol. 9, issue 1, 1-11

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41467-018-06890-y

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