2024-06-10 カリフォルニア大学校アーバイン校(UCI)
<関連情報>
- https://news.uci.edu/2024/06/10/cutting-the-cable-between-cd8-t-and-t-regulatory-cells-enhances-checkpoint-immunotherapy/
- https://www.cell.com/cancer-cell/abstract/S1535-6108(24)00181-8
腫瘍内CD8+ T細胞とTregのクロストークを遮断するとPD-1免疫療法の有効性が改善する Interruption of the intratumor CD8+ T cell:Treg crosstalk improves the efficacy of PD-1 immunotherapy
Shannon N. Geels,Alexander Moshensky,Rachel S. Sousa,…,Anand K. Ganesan,Shivashankar Othy,Francesco Marangoni
Cancer Cell Published:June 10, 2024
DOI:https://doi.org/10.1016/j.ccell.2024.05.013
Highlights
- PD-1 blockade expands Tregs in melanoma and limits the efficacy of immunotherapy
- Treg-intrinsic PD-1 inhibition does not cause tumor-Treg accumulation
- αPD-1 increases Treg numbers via an intratumor CD8+ T cell/IL-2/ICOS axis
- Inhibition of the CD8+T cell:Treg crosstalk by αICOSL synergizes with αPD-1 therapy
Summary
PD-1 blockade unleashes potent antitumor activity in CD8+ T cells but can also promote immunosuppressive T regulatory (Treg) cells, which may worsen the response to immunotherapy. Tumor-Treg inhibition is a promising strategy to improve the efficacy of checkpoint blockade immunotherapy; however, our understanding of the mechanisms supporting tumor-Tregs during PD-1 immunotherapy is incomplete. Here, we show that PD-1 blockade increases tumor-Tregs in mouse models of melanoma and metastatic melanoma patients. Mechanistically, Treg accumulation is not caused by Treg-intrinsic inhibition of PD-1 signaling but depends on an indirect effect of activated CD8+ T cells. CD8+ T cells produce IL-2 and colocalize with Tregs in mouse and human melanomas. IL-2 upregulates the anti-apoptotic protein ICOS on tumor-Tregs, promoting their accumulation. Inhibition of ICOS signaling before PD-1 immunotherapy improves control over immunogenic melanoma. Thus, interrupting the intratumor CD8+ T cell:Treg crosstalk represents a strategy to enhance the therapeutic efficacy of PD-1 immunotherapy.
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