Abstract
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阻断可释放CD8+ T细胞的强大抗肿瘤活性，但也会促进免疫抑制性调节性T细胞（Treg），从而可能会恶化对免疫疗法的反应。抑制肿瘤-Treg是提高检查点阻断免疫疗法疗效的一种很有前景的策略；然而，我们对PD-1免疫疗法期间支持肿瘤-Treg的机制的了解还不全面。在这里，我们发现在黑色素瘤小鼠模型和转移性黑色素瘤患者中，PD-1阻断会增加肿瘤-Tregs。从机理上讲，Treg的积累并不是由PD-1信号的Treg内在抑制引起的，而是取决于活化的CD8+ T细胞的间接作用。CD8+ T细胞产生IL-2，并与小鼠和人类黑色素瘤中的Tregs共定位。IL-2上调肿瘤-Tregs上的抗凋亡蛋白ICOS，促进它们的聚集。在PD-1免疫疗法之前抑制ICOS信号传导可改善对免疫原性黑色素瘤的控制。因此，阻断肿瘤内CD8+ T细胞与Treg的串扰是提高PD-1免疫疗法疗效的一种策略。
Geels SN, Moshensky A, Sousa RS, Murat C, Bustos MA, Walker BL, Singh R, Harbour SN, Gutierrez G, Hwang M, Mempel TR, Weaver CT, Nie Q, Hoon DSB, Ganesan AK, Othy S, Marangoni F. Interruption of the intratumor CD8+ T cell:Treg crosstalk improves the efficacy of PD-1 immunotherapy. Cancer Cell. 2024 Jun 10;42(6):1051-1066.e7. doi: 10.1016/j.ccell.2024.05.013. PMID: 38861924.
