Targeting IL-21 to tumor-reactive T cells enhances memory T cell responses and anti-PD-1 antibody therapy

Ying Li (), Yanni Cong, Mingming Jia, Qianqian He, Haiqing Zhong, Yun Zhao, Hang Li, Meining Yan, Jia You, Jia Liu, Lieping Chen, Haiying Hang and Shengdian Wang ()
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Ying Li: Institute of Biophysics, Chinese Academy of Sciences
Yanni Cong: Institute of Biophysics, Chinese Academy of Sciences
Mingming Jia: Institute of Biophysics, Chinese Academy of Sciences
Qianqian He: Institute of Biophysics, Chinese Academy of Sciences
Haiqing Zhong: Institute of Biophysics, Chinese Academy of Sciences
Yun Zhao: Institute of Biophysics, Chinese Academy of Sciences
Hang Li: Institute of Biophysics, Chinese Academy of Sciences
Meining Yan: Institute of Biophysics, Chinese Academy of Sciences
Jia You: Institute of Biophysics, Chinese Academy of Sciences
Jia Liu: Institute of Biophysics, Chinese Academy of Sciences
Lieping Chen: Yale University
Haiying Hang: University of the Chinese Academy of Sciences, Chinese Academy of Sciences
Shengdian Wang: Institute of Biophysics, Chinese Academy of Sciences

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: Abstract T cell rejuvenation by PD-1/PD-L1 blockade, despite emerging as a highly promising therapy for advanced cancers, is only beneficial for a minority of treated patients. There is evidence that a lack of efficient T cell activation may be responsible for the failure. Here, we demonstrate that IL-21 can be targeted to tumor-reactive T cells by fusion of IL-21 to anti-PD-1 antibody. To our surprise, the fusion protein PD-1Ab21 promotes the generation of memory stem T cells (TSCM) with enhanced cell proliferation. PD-1Ab21 treatment show potent antitumor effects in established tumor-bearing mice accompanied with an increased frequency of TSCM and robust expansion of tumor-specific CD8+ T cells with a memory phenotype, and is superior to a combination of PD-1 blockade and IL-21 infusion. Therefore, we have developed a potential strategy to improve the therapeutic effects of immune checkpoint blockade by simultaneously targeting cytokines to tumor-reactive T cells.

Date: 2021
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DOI: 10.1038/s41467-021-21241-0

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