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

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 l...

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Bibliographic Details
Published in:The Journal of clinical investigation 2022-02, Vol.132 (3), p.1-13
Main Authors: Ren, Zhenhua, Zhang, Anli, Sun, Zhichen, Liang, Yong, Ye, Jianfeng, Qiao, Jian, Li, Bo, Fu, Yang-Xin
Format: Article
Language:English
Subjects:
Affinity
Animals
Antibodies
Avidity
Biomedical research
Cancer therapies
CD8 antigen
CD8-Positive T-Lymphocytes - immunology
Cell growth
Immunity, Cellular - drug effects
Immunity, Cellular - genetics
Immunology
Immunotherapy
Interleukin 2
Interleukin-2 - genetics
Interleukin-2 - pharmacology
Lymphocytes
Lymphocytes T
Lymphocytes, Tumor-Infiltrating - immunology
Mice
Mice, Inbred BALB C
Mice, Knockout
Neoplasms, Experimental - genetics
Neoplasms, Experimental - immunology
Neoplasms, Experimental - therapy
PD-1 protein
Programmed Cell Death 1 Receptor - genetics
Programmed Cell Death 1 Receptor - immunology
Toxicity
Tumor-infiltrating lymphocytes
Tumors
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Summary: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.
ISSN:1558-8238
0021-9738
1558-8238
DOI:10.1172/JCI153604