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 - 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 -