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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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 1

PD-1–laIL-2 selectively targets intratumoral CD8+ T cells.

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PD-1–laIL-2 selectively targets intratumoral CD8+ T cells. (A) BALB/c mi...
(A) BALB/c mice (n = 5/group) were inoculated with 2 × 106 A20 tumor cells and were treated with 50 μg anti–PD-1 and/or 200 μg anti–IL-2Rβ on day 14. Tumor growth was assessed twice a week. (B) IL-2Rα expression on CD8+, CD4+, and Treg cells in peripheral blood, spleen, and tumor samples (indicated as PB, SP, and tumor in the figures) from A20 tumor-bearing mice (n = 5/group). (C) Percentages of PD-1+ T cells in peripheral blood, spleen, and tumor samples from A20 tumor-bearing mice (n = 5/group). (D) Mean fluorescence intensity (MFI) of PD-1 on Treg and CD8+ T cells in the spleen and on Treg and PD-1+CD8+ T cells in the tumors from A20 tumor-bearing mice (n = 5/group). (E) Schematic diagram of the anti–PD-1 × laIL-2 heterodimer (PD-1–laIL-2). (F and G) PD-1–wtIL-2 and PD-1–laIL-2 bind to Treg (F), CD8+, and CD4+ (G) T cells in the spleen of A20 tumor-bearing mice (n = 5/group). (H) Erb–laIL-2 and PD-1–laIL-2 bind to PD-1+CD8+ T cells in tumors from A20 tumor-bearing mice (n = 5/group). (I) PD-1–laIL-2 binds to CD8+ T cells in the spleen and to PD-1+CD8+ T cells in tumors from A20 tumor-bearing mice (n = 5/group). (J) PD-1–laIL-2 binds to PD-1–CD8+ and PD-1+CD8+ T cells in tumors from A20 tumor-bearing mice (n = 5/group). Data represent mean ± SEM from 2 to 3 independent experiments. The P value was determined by 2-way ANOVA with Geisser-Greenhouse’s correction (A), 1-way ANOVA with Tukey’s multiple comparisons test (D and H), 2-way ANOVA with Tukey’s multiple comparisons test (G and I), or 2-tailed unpaired t test (J). The normality of the data was confirmed by the Shapiro-Wilk test. ***P < 0.001, ****P < 0.0001.