Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University School of Pharmacy, Shanghai, China.
College of Literature, Science, and the Arts, University of Michigan, Ann Arbor, Michigan, USA.
J Immunother Cancer. 2024 Sep 3;12(9):e009236. doi: 10.1136/jitc-2024-009236.
The main challenge against patients with cancer to derive benefits from immune checkpoint inhibitors targeting PD-1/PD-L1 appears to be the immunosuppressive tumor microenvironment (TME), in which IL-33/ST2 signal fulfills critical functions. However, whether IL-33 limits the therapeutic efficacy of anti-PD-L1 remains uncertain.
Molecular mechanisms of IL-33/ST2 signal on anti-PD-L1 treatment lewis lung carcinoma tumor model were assessed by RNA-seq, ELISA, WB and immunofluorescence (IF). A sST2-Fc fusion protein was constructed for targeting IL-33 and combined with anti-PD-L1 antibody for immunotherapy in colon and lung tumor models. On this basis, bifunctional fusion proteins were generated for PD-L1-targeted blocking of IL-33 in tumors. The underlying mechanisms of dual targeting of IL-33 and PD-L1 revealed by RNA-seq, scRNA-seq, FACS, IF and WB.
After anti-PD-L1 administration, tumor-infiltrating ST2 regulatory T cells (Tregs) were elevated. Blocking IL-33/ST2 signal with sST2-Fc fusion protein potentiated antitumor efficacy of PD-L1 antibody by enhancing T cell responses in tumor models. Bifunctional fusion protein anti-PD-L1-sST2 exhibited enhanced antitumor efficacy compared with combination therapy, not only inhibited tumor progression and extended the survival, but also provided long-term protective antitumor immunity. Mechanistically, the superior antitumor activity of targeting IL-33 and PD-L1 originated from reducing immunosuppressive factors, such as Tregs and exhausted CD8 T cells while increasing tumor-infiltrating cytotoxic T lymphocyte cells.
In this study, we demonstrated that IL-33/ST2 was involved in the immunosuppression mechanism of PD-L1 antibody therapy, and blockade by sST2-Fc or anti-PD-L1-sST2 could remodel the inflammatory TME and induce potent antitumor effect, highlighting the potential therapeutic strategies for the tumor treatment by simultaneously targeting IL-33 and PD-L1.
针对 PD-1/PD-L1 的免疫检查点抑制剂在癌症患者中获益的主要挑战似乎是免疫抑制性肿瘤微环境 (TME)，其中 IL-33/ST2 信号发挥关键作用。然而，IL-33 是否限制抗 PD-L1 的治疗效果尚不确定。
通过 RNA-seq、ELISA、WB 和免疫荧光 (IF) 评估 IL-33/ST2 信号对抗 PD-L1 治疗 Lewis 肺癌肿瘤模型的分子机制。构建 sST2-Fc 融合蛋白以靶向 IL-33，并将其与抗 PD-L1 抗体结合用于结肠和肺癌肿瘤模型的免疫治疗。在此基础上，生成用于肿瘤中 IL-33 靶向阻断的 PD-L1 双功能融合蛋白。通过 RNA-seq、scRNA-seq、FACS、IF 和 WB 揭示了双重靶向 IL-33 和 PD-L1 的潜在机制。
抗 PD-L1 给药后，肿瘤浸润性 ST2 调节性 T 细胞 (Treg) 升高。用 sST2-Fc 融合蛋白阻断 IL-33/ST2 信号通过增强肿瘤模型中的 T 细胞反应增强了 PD-L1 抗体的抗肿瘤疗效。与联合治疗相比，双功能融合蛋白抗 PD-L1-sST2 表现出增强的抗肿瘤疗效，不仅抑制肿瘤进展和延长生存时间，而且提供长期保护性抗肿瘤免疫。从机制上讲，靶向 IL-33 和 PD-L1 的抗肿瘤活性源于减少免疫抑制因子，如 Tregs 和耗竭的 CD8 T 细胞，同时增加肿瘤浸润性细胞毒性 T 淋巴细胞细胞。
在这项研究中，我们证明了 IL-33/ST2 参与了 PD-L1 抗体治疗的免疫抑制机制，sST2-Fc 或抗 PD-L1-sST2 的阻断可以重塑炎症性 TME 并诱导强大的抗肿瘤作用，突出了同时靶向 IL-33 和 PD-L1 的肿瘤治疗的潜在治疗策略。
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