Institute for Immunology, University of California, Irvine, Irvine, CA, USA; Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA, USA.
Institute for Immunology, University of California, Irvine, Irvine, CA, USA; Center for Complex Biological Systems, University of California, Irvine, Irvine, CA, USA; NSF-Simons Center for Multiscale Cell Fate Research, University of California, Irvine, Irvine, CA, USA.
Cancer Cell. 2024 Jun 10;42(6):1051-1066.e7. doi: 10.1016/j.ccell.2024.05.013.
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.
PD-1 阻断在 CD8 T 细胞中释放出强大的抗肿瘤活性，但也可促进免疫抑制性 T 调节（Treg）细胞，这可能会使免疫疗法的反应恶化。肿瘤-Treg 抑制是一种提高检查点阻断免疫疗法疗效的有前途的策略；然而，我们对 PD-1 免疫疗法期间支持肿瘤-Tregs 的机制了解还不完整。在这里，我们表明 PD-1 阻断会增加黑色素瘤小鼠模型和转移性黑色素瘤患者中的肿瘤-Tregs。从机制上讲，Treg 的积累不是由 Treg 内在的 PD-1 信号抑制引起的，而是依赖于活化的 CD8 T 细胞的间接作用。CD8 T 细胞在小鼠和人类黑色素瘤中产生 IL-2 并与 Treg 共定位。IL-2 上调肿瘤-Tregs 上的抗凋亡蛋白 ICOS，促进其积累。在 PD-1 免疫治疗之前抑制 ICOS 信号可改善对免疫原性黑色素瘤的控制。因此，中断肿瘤内 CD8 T 细胞：Treg 串扰代表了增强 PD-1 免疫疗法治疗效果的一种策略。
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