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 3

Antitumor efficacy of PD-1–laIL-2 depends on intratumoral CD8+ T cells.

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Antitumor efficacy of PD-1–laIL-2 depends on intratumoral CD8+ T cells. ...
(A) A20 tumor-bearing Rag1-KO mice (n = 5/group) were treated with 20 μg PD-1–laIL-2 on day 15. Tumor growth was assessed twice a week. (B) A20 tumor-bearing mice (n = 5/group) were treated with 20 μg PD-1–laIL-2 on day 17. Anti-CD8 (200 μg/mouse) was administered twice a week starting on day 16. Tumor growth was assessed twice a week. (C) A20 tumor-bearing mice (n = 5/group) were treated with 20 μg PD-1–laIL-2 on day 17. FTY720 was administered every 2 days starting on day 16 through the end of the experiment. Tumor growth was assessed twice a week. (D) A20 tumor-bearing mice (n = 5/group) were treated with 20 μg PD-1–laIL-2 on day 17. FTY720 was administered every 2 days starting on day 16 through the end of the experiment. Anti-CD8 (200 μg/mouse) was administered twice a week starting on day 16. Tumor growth was assessed twice a week. (E) Renca tumor-bearing mice (n = 5/group) were treated with 100 μg PD-1–laIL-2 or PD-1–wtIL-2 intraperitoneally. Mouse body weight was monitored twice a week. (F) Renca tumor-bearing mice (n = 5/group) were treated with equal molar amounts of Erb–laIL-2 (100 μg), anti–PD-1 (50 μg), PD-1–laIL-2 (100 μg), or PD-1–wtIL-2 (100 μg) by intraperitoneal injection. IFN-γ in the serum was measured by cytometric bead array (CBA) one day after the treatment. Data represent mean ± SEM from 2 independent experiments. The P value was determined by 2-way ANOVA with Geisser-Greenhouse correction (A–E) or 2-way ANOVA with Tukey’s multiple comparisons test (F). ****P < 0.0001.