Selective delivery of low-affinity IL-2 to PD-1+ T cells rejuvenates antitumor immunity with reduced toxicity
Zhenhua Ren, … , Bo Li, Yang-Xin Fu
Zhenhua Ren, … , Bo Li, Yang-Xin Fu
Published February 1, 2022
Citation Information: J Clin Invest. 2022;132(3):e153604. https://doi.org/10.1172/JCI153604.
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Research Article Immunology

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

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.

Authors

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

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Figure 7

PD-1–laIL-2 specifically reactivates PD-1+TIM3+ tumor-specific CD8+ T cells.

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PD-1–laIL-2 specifically reactivates PD-1+TIM3+ tumor-specific CD8+ T ce...
(A–D) CD4+, PD-1–CD8+, PD-1+TIM3–CD8+, and PD-1+TIM3+CD8+ T cells from A20 tumor-bearing mice were sorted out and cocultured with irradiated A20 cells in the presence of Erb–laIL-2 or PD-1–laIL-2 for the IFN-γ ELISPOT assay. Experimental scheme (A) and spots from PD-1–CD8+ (B), PD-1+TIM3–CD8+ (C) and PD-1+TIM3+CD8+ (D) T cells are shown. (E) PD-1 and TIM3 expressions on tetramer+CD8+ T cells in tumors from MC38 tumor-bearing mice (n = 5). (F–I) Splenocytes were stimulated with anti-CD3 and anti-CD28 antibodies. Five days later, PD-1+TIM3+CD8+ T cells were sorted out and labeled with CFSE. Then, the cells were cultured in 96-well plates in the presence of anti-CD3, Erb–laIL-2 plus anti–PD-1 (combo), or PD-1–laIL-2 for 2 days. The T cell clusters and CFSE expression were assayed with an Incucyte instrument. Total areas of the cluster are shown in F. Mean CFSE intensity is shown in G. (H) Percentage of CFSE low cells. (I) MFI of CFSE low cells. (J) A20 tumor-bearing mice (n = 5/group) were treated with equal molar amounts of Erb–laIL-2 (20 μg), anti–PD-1 (10 μg), or PD-1–laIL-2 (20 μg) on day 19. Six days later, T cells from the tumor were analyzed. Data represent mean ± SEM. The P value was determined by 2-way ANOVA with Tukey’s multiple comparisons test (D) or 1-way ANOVA with Tukey’s multiple comparisons test (E–J). *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001.