Targeting tumors with IL-21 reshapes the tumor microenvironment by proliferating PD-1intTim-3-CD8+ T cells

Sisi Deng, Zhichen Sun, Jian Qiao, Yong Liang, Longchao Liu, Chunbo Dong, Aijun Shen, Yang Wang, Hong Tang, Yang Xin Fu, Hua Peng

Research output: Contribution to journalArticle

Abstract

The lack of sufficient functional tumor-infiltrating lymphocytes in the tumor microenvironment (TME) is one of the primary indications for the poor prognosis of patients with cancer. In this study, we developed an Erbitux-based IL-21 tumor-targeting fusion protein (Erb-IL21) to prolong the half-life and improve the antitumor efficacy of IL-21. Compared with Erb-IL2, ErbIL21 demonstrated much lower toxicity in vivo. Mechanistically, Erb-IL21 selectively expanded functional cytotoxic T lymphocytes but not dysfunctional CD8+ T cells in the TME. We observed that the IL-21-mediated antitumor effect largely depended on the existing intratumoral CD8+ T cells, instead of newly migrated CD8+ T cells. Furthermore, Erb-IL21 overcame checkpoint blockade resistance in mice with advanced tumors. Our study reveals that Erb-IL21 can target IL-21 to tumors and maximize the antitumor potential of checkpoint blockade by expending a subset of tumor antigen-specific CD8+ T cells to achieve effective tumor control.

Original languageEnglish (US)
Article numbere132000
JournalJCI Insight
Volume5
Issue number7
DOIs
StatePublished - Apr 2020

ASJC Scopus subject areas

  • Medicine(all)

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    Deng, S., Sun, Z., Qiao, J., Liang, Y., Liu, L., Dong, C., Shen, A., Wang, Y., Tang, H., Fu, Y. X., & Peng, H. (2020). Targeting tumors with IL-21 reshapes the tumor microenvironment by proliferating PD-1intTim-3-CD8+ T cells. JCI Insight, 5(7), [e132000]. https://doi.org/10.1172/JCI.INSIGHT.132000