Selective delivery of low-affinity IL-2 to PD-1+ T cells rejuvenates antitumor immunity with reduced toxicity

Zhenhua Ren, Anli Zhang, Zhichen Sun, Yong Liang, Jianfeng Ye, Jian Qiao, Bo Li, Yang Xin Fu

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

PD-1 signaling on T cells is the major pathway that limits T cell immunity, but the efficacy of anti–PD-1 therapy has been limited to a small proportion of patients with advanced cancers. We fortuitously observed that anti–PD-1 therapy depends on IL-2 signaling, which raises the possibility that a lack of IL-2 limits anti–PD-1–induced effector T cell expansion. To selectively deliver IL-2 to PD-1+CD8+ tumor-infiltrating lymphocytes (TILs), we engineered a low-affinity IL-2 paired with anti–PD-1 (PD-1–laIL-2), which reduced affinity to peripheral Treg cells but enhanced avidity to PD-1+CD8+ TILs. PD-1–laIL-2 exerted better tumor control and lower toxicity than single or mixed treatments. Mechanistically, PD-1–laIL-2 could effectively expand dysfunctional and tumor-specific CD8+ T cells. Furthermore, we discovered that presumably dysfunctional PD-1+TIM3+ TILs are the dominant tumor-specific T cells responding to PD-1–laIL-2. Collectively, these results highlight that PD-1–laIL-2 can target and reactivate tumor-specific TILs for tumor regression as a unique strategy with stronger efficacy and lower toxicity.

Original languageEnglish (US)
Article numbere153604
JournalJournal of Clinical Investigation
Volume132
Issue number3
DOIs
StatePublished - Feb 1 2022

ASJC Scopus subject areas

  • Medicine(all)

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