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

Affiliation

Li Y(#)(1), Cong Y(#)(2)(3), Jia M(2), He Q(2)(3), Zhong H(2)(3), Zhao Y(4), Li H(2), Yan M(2), You J(2), Liu J(2)(3), Chen L(5), Hang H(3)(4), Wang S(6)(7).
Author information:
(1)CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China. [Email]
(2)CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
(3)University of the Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing, China.
(4)Key Laboratory of Protein and Peptide Pharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
(5)Department of Immunobiology and Yale Cancer Center, Yale University, New Haven, CT, USA.
(6)CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China. [Email]
(7)University of the Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing, China. [Email]
(#)Contributed equally

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.