联合与征服：锰协同抗 TGF-β/PD-L1 双特异性抗体 YM101 克服非炎症性癌症的免疫治疗耐药性。
Combine and conquer: manganese synergizing anti-TGF-β/PD-L1 bispecific antibody YM101 to overcome immunotherapy resistance in non-inflamed cancers.
机构信息
Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, People's Republic of China.
Wuhan YZY Biopharma Co., Ltd, Biolake, C2-1, No.666 Gaoxin Road, Wuhan, 430075, People's Republic of China.
出版信息
J Hematol Oncol. 2021 Sep 15;14(1):146. doi: 10.1186/s13045-021-01155-6.
BACKGROUND
Our previous work showed that the anti-TGF-β/PD-L1 bispecific antibody YM101 effectively overcame anti-PD-L1 resistance in immune-excluded tumor models. However, in immune-desert models, the efficacy of YM101 was limited. Bivalent manganese (Mn) is identified as a natural stimulator of interferon genes (STING) agonist, which might enhance cancer antigen presentation and improve the therapeutic effect of YM101.
METHODS
The effect of Mn on STING pathway was validated by western blotting and enzyme-linked immunosorbent assay. Dendritic cell (DC) maturation was measured by flow cytometry. The synergistic effect between Mn and YM101 in vitro was determined by one-way mixed lymphocyte reaction, CFSE dilution assay, and cytokine detection. The in vivo antitumor effect of Mn plus YM101 therapy was assessed in CT26, EMT-6, H22, and B16 tumor models. Flow cytometry, RNA-seq, and immunofluorescent staining were adopted to investigate the alterations in the tumor microenvironment.
RESULTS
Mn could activate STING pathway and promote the maturation of human and murine DC. The results of one-way mixed lymphocyte reaction showed that Mn synergized YM101 in T cell activation. Moreover, in multiple syngeneic murine tumor models, Mn plus YM101 therapy exhibited a durable antitumor effect and prolonged the survival of tumor-bearing mice. Relative to YM101 monotherapy and Mn plus anti-PD-L1 therapy, Mn plus YM101 treatment had a more powerful antitumor effect and a broader antitumor spectrum. Mechanistically, Mn plus YM101 strategy simultaneously regulated multiple components in the antitumor immunity and drove the shift from immune-excluded or immune-desert to immune-inflamed tumors. The investigation in the TME indicated Mn plus YM101 strategy activated innate and adaptive immunity, enhanced cancer antigen presentation, and upregulated the density and function of tumor-infiltrating lymphocytes. This normalized TME and reinvigorated antitumor immunity contributed to the superior antitumor effect of the combination therapy.
CONCLUSION
Combining Mn with YM101 has a synergistic antitumor effect, effectively controlling tumor growth and prolonging the survival of tumor-bearing mice. This novel cocktail strategy has the potential to be a universal regimen for inflamed and non-inflamed tumors.
背景
我们之前的工作表明，抗 TGF-β/PD-L1 双特异性抗体 YM101 有效地克服了免疫排斥肿瘤模型中的抗 PD-L1 耐药性。然而，在免疫荒漠模型中，YM101 的疗效有限。二价锰（Mn）被鉴定为干扰素基因（STING）激动剂的天然刺激物，它可能增强癌症抗原呈递并提高 YM101 的治疗效果。
方法
通过 Western blot 和酶联免疫吸附试验验证 Mn 对 STING 通路的影响。通过流式细胞术测量树突状细胞（DC）成熟。通过单向混合淋巴细胞反应、CFSE 稀释试验和细胞因子检测确定 Mn 与 YM101 体外的协同作用。在 CT26、EMT-6、H22 和 B16 肿瘤模型中评估 Mn 加 YM101 治疗的体内抗肿瘤作用。采用流式细胞术、RNA-seq 和免疫荧光染色来研究肿瘤微环境的变化。
结果
Mn 可以激活 STING 通路并促进人源和鼠源 DC 的成熟。单向混合淋巴细胞反应的结果表明，Mn 协同 YM101 激活 T 细胞。此外，在多种同源小鼠肿瘤模型中，Mn 加 YM101 治疗表现出持久的抗肿瘤作用，并延长荷瘤小鼠的存活时间。与 YM101 单药治疗和 Mn 加抗 PD-L1 治疗相比，Mn 加 YM101 治疗具有更强的抗肿瘤作用和更广泛的抗肿瘤谱。机制上，Mn 加 YM101 策略同时调节抗肿瘤免疫中的多个成分，并促使肿瘤从免疫排斥或免疫荒漠向免疫炎症转变。在 TME 中的研究表明，Mn 加 YM101 策略激活了先天和适应性免疫，增强了癌症抗原呈递，并上调了肿瘤浸润淋巴细胞的密度和功能。这种正常化的 TME 和重新激活的抗肿瘤免疫有助于联合治疗的优越抗肿瘤效果。
结论
Mn 与 YM101 联合具有协同的抗肿瘤作用，有效控制肿瘤生长并延长荷瘤小鼠的存活时间。这种新型鸡尾酒策略有可能成为一种适用于炎症和非炎症肿瘤的通用方案。
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