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 M Dong, Hua Peng, Yang Xin Fu

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Article number4586
JournalNature Communications
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2018

Fingerprint

interferon
Interferons
Tumors
tumors
T-cells
T-Lymphocytes
Neoplasms
Antigen Presentation
antigens
Up-Regulation
antibodies
Tumor-Infiltrating Lymphocytes
Interferon Type I
Antibodies
Chemical activation
Cells
Neoplasm Antigens
activation
Protein Transport
Antigens

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Targeting IFNα to tumor by anti-PD-L1 creates feedforward antitumor responses to overcome checkpoint blockade resistance. / Liang, Yong; Tang, Haidong; Guo, Jingya; Qiu, Xiangyan; Yang, Zecheng; Ren, Zhenhua; Sun, Zhichen; Bian, Yingjie; Xu, Lily; Xu, Hairong; Shen, Jiao; Han, Yanfei; Dong, Haidong M; Peng, Hua; Fu, Yang Xin.

In: Nature Communications, Vol. 9, No. 1, 4586, 01.12.2018.

Research output: Contribution to journalArticle

Liang, Y, Tang, H, Guo, J, Qiu, X, Yang, Z, Ren, Z, Sun, Z, Bian, Y, Xu, L, Xu, H, Shen, J, Han, Y, Dong, HM, Peng, H & Fu, YX 2018, 'Targeting IFNα to tumor by anti-PD-L1 creates feedforward antitumor responses to overcome checkpoint blockade resistance', Nature Communications, vol. 9, no. 1, 4586. https://doi.org/10.1038/s41467-018-06890-y
Liang, Yong ; Tang, Haidong ; Guo, Jingya ; Qiu, Xiangyan ; Yang, Zecheng ; Ren, Zhenhua ; Sun, Zhichen ; Bian, Yingjie ; Xu, Lily ; Xu, Hairong ; Shen, Jiao ; Han, Yanfei ; Dong, Haidong M ; Peng, Hua ; Fu, Yang Xin. / Targeting IFNα to tumor by anti-PD-L1 creates feedforward antitumor responses to overcome checkpoint blockade resistance. In: Nature Communications. 2018 ; Vol. 9, No. 1.
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