PDF(Pubmed)
Abstract：
Rationale: An immunosuppressive tumor microenvironment (TME) is a major obstacle in tumor immunotherapy. Stimulator of interferon genes (STING) agonists trigger an inflammatory innate immune response to potentially overcome tumor immunosuppression. While STING agonists may hold promise as potential cancer therapy agents, tumor resistance to STING monotherapy has emerged in clinical trials, and the mechanisms remain unclear. Methods: The in vivo anti-tumor immunity of STING agonist ADU-S100 (S100), plus anti-T cell immunoglobulin and mucin-domain containing-3 antibody (αTim-3) were measured using murine tumor models. Tumor-specific T cell activation and alterations in the TME were detected using flow cytometry. The maturation and function of dendritic cells (DC) were also measured using flow cytometry, and the importance of CD4+ T cells in combination therapy was measured by blocking antibodies. Additionally, the effect of S100 on CD4+ T was verified via in vitro assays. Lastly, the impact of conventional dendritic cells (cDC) 2 with a high expression of Tim-3 on survival or therapeutic outcomes was further evaluated in human tumor samples. Results: S100 boosted CD8+ T by activating cDC1 but failed to initiate cDC2. Mechanistically, the administration of S100 results in an upregulation of Tim-3 expressed in cDC2 (Tim-3+cDC2) in both mice and humans, which is immunosuppressive. Tim-3+cDC2 restrained CD4+ T and attenuated the CD4+ T-driven anti-tumor response. Combining S100 with αTim-3 effectively promoted cDC2 maturation and antigen presentation, releasing CD4+ T cells, thus reducing tumor burden while prolonging survival. Furthermore, high percentages of Tim-3+cDC2 in the human TME predicted poor prognosis, whereas the abundance of Tim-3+cDC2 may act as a biomarker for CD4+ T quality and a contributing indicator for responsiveness to immunotherapy. Conclusion: This research demonstrated that blocking Tim-3 could enhance the anti-tumor immunity of STING agonist ADU-S100 by releasing CD4+ T cells through regulating cDC2. It also revealed an intrinsic barrier to ADU-S100 monotherapy, besides providing a combinatorial strategy for overcoming immunosuppression in tumors.
摘要：
原理：免疫抑制性肿瘤微环境（TME）是肿瘤免疫治疗的主要障碍。干扰素基因的刺激物(STING)激动剂触发炎性先天免疫应答以潜在地克服肿瘤免疫抑制。虽然STING激动剂可能有望成为潜在的癌症治疗剂，肿瘤对STING单一疗法的耐药性已经出现在临床试验中，机制尚不清楚。方法:STING激动剂ADU-S100(S100)体内抗肿瘤免疫,使用鼠肿瘤模型测量了抗T细胞免疫球蛋白和含粘蛋白结构域的3抗体（αTim-3）。使用流式细胞术检测肿瘤特异性T细胞活化和TME中的改变。还使用流式细胞术测量了树突状细胞（DC）的成熟和功能，CD4+T细胞在联合治疗中的重要性通过阻断抗体来衡量。此外,通过体外试验验证了S100对CD4+T的影响。最后,在人肿瘤样本中进一步评估了Tim-3高表达的常规树突状细胞(cDC)2对生存或治疗结果的影响.结果:S100通过激活cDC1增强CD8+T,但未能启动cDC2。机械上,S100的给药导致小鼠和人类中在cDC2中表达的Tim-3(Tim-3+cDC2)上调,具有免疫抑制作用.Tim-3+cDC2抑制CD4+T并减弱CD4+T驱动的抗肿瘤反应。S100与αTim-3联合有效促进cDC2成熟和抗原呈递,释放CD4+T细胞，从而减少肿瘤负担，同时延长生存期。此外，人类TME中Tim-3+cDC2的高百分比预测预后不良，而Tim-3+cDC2的丰度可能是CD4+T质量的生物标志物和免疫疗法反应性的重要指标.结论：本研究表明，阻断Tim-3可以通过调节cDC2释放CD4T细胞来增强STING激动剂ADU-S100的抗肿瘤免疫力。它还揭示了ADU-S100单药治疗的内在障碍，除了提供克服肿瘤免疫抑制的组合策略。
