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

Ying Li,Meining Yan,Jia You,Haiqing Zhong,Qianqian He,Yun Zhao,Lieping Chen,Shengdian Wang,Jia Liu,Hang Li,Yanni Cong,Mingming Jia,Haiying Hang

doi:10.1038/s41467-021-21241-0

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.

Highlights

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
PD-1Ab21 had the same effect on the proliferation of the pro-B cell line Baf[3] as recombinant IL-21 (Fig. 1e). These results demonstrate that PD-1Ab21 can bind PD-1 on activated T cells to block the interaction of PD-1 with PD-L1 while maintaining IL-21 bioactivity
We engineered an antiPD-1 antibody-based immunocytokine, denoted as PD-1Ab21, by fusing IL-21 to anti-PD-1 diabody to illustrate that cytokines can be targeted to tumor-reactive T cells in vivo to promote cancer immunotherapy

Summary

Introduction

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. We have developed a potential strategy to improve the therapeutic effects of immune checkpoint blockade by simultaneously targeting cytokines to tumor-reactive T cells. As our understanding of the response or resistance to PD-1 blockade continues to evolve, it is generally recognized that successful antitumor immune responses following PD-1 blockade require reactivation and proliferation of antigen-experienced CD8+ T cells present in the tumor microenvironment (TME)[4] In this respect, the γc family cytokines, especially IL-2, IL-15, and IL-21, play an important role in regulating the magnitude and function of CD8+ T cell response[7]. Tumor-specific CD8+ T cell express a high level of PD-1, and the presence of PD-1 can identify the repertoire of tumor-reactive CD8+ T lymphocytes[20,21]. We hypothesize that the fusion of IL-21 to anti-PD-1 antibody will concentrate IL-21 to PD-1+ T cells in vivo, which can greatly increase the effect of IL-21 on tumor-specific T cells while reducing its side effects

Methods

Results

Conclusion