干旱区生态环境知识资源中心(Arid): Combine and conquer: manganese synergizing anti-TGF-beta/PD-L1 bispecific antibody YM101 to overcome immunotherapy resistance in non-inflamed cancers

Arid

DOI	10.1186/s13045-021-01155-6
	Combine and conquer: manganese synergizing anti-TGF-beta/PD-L1 bispecific antibody YM101 to overcome immunotherapy resistance in non-inflamed cancers
	Yi, Ming; Niu, Mengke; Zhang, Jing; Li, Shiyu; Zhu, Shuangli; Yan, Yongxiang; Li, Ning; Zhou, Pengfei; Chu, Qian; Wu, Kongming
通讯作者	Wu, KM (corresponding author), Huazhong Univ Sci & Technol, Tongji Med Coll, Dept Oncol, Tongji Hosp, 1095 Jiefang Ave, Wuhan 430030, Peoples R China. ; Wu, KM (corresponding author), Zhengzhou Univ, Dept Med Oncol, Affiliated Canc Hosp, Zhengzhou 450008, Peoples R China. ; Wu, KM (corresponding author), Henan Canc Hosp, Zhengzhou 450008, Peoples R China.
来源期刊	JOURNAL OF HEMATOLOGY & ONCOLOGY
EISSN	1756-8722
出版年	2021
卷号	14 期号:1
英文摘要	Background: Our previous work showed that the anti-TGF-beta/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 (Mn2+) 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 Mn2+ 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 Mn2+ and YM101 in vitro was determined by one-way mixed lymphocyte reaction, CFSE dilution assay, and cytokine detection. The in vivo antitumor effect of Mn2+ 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: Mn2+ could activate STING pathway and promote the maturation of human and murine DC. The results of one-way mixed lymphocyte reaction showed that Mn2+ synergized YM101 in T cell activation. Moreover, in multiple syngeneic murine tumor models, Mn2+ plus YM101 therapy exhibited a durable antitumor effect and prolonged the survival of tumor-bearing mice. Relative to YM101 monotherapy and Mn2+ plus anti-PD-L1 therapy, Mn2+ plus YM101 treatment had a more powerful antitumor effect and a broader antitumor spectrum. Mechanistically, Mn2+ 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 Mn2+ 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 Mn2+ 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.
英文关键词	The tumor microenvironment Manganese cGAS-STING PD-L1 TGF-beta Bispecific antibody Cancer immunotherapy
类型	Article
语种	英语
开放获取类型	Green Published, gold
收录类别	SCI-E
WOS记录号	WOS:000696237000002
WOS关键词	BLOCKADE ; IMMUNITY ; THERAPY
WOS类目	Oncology ; Hematology
WOS研究方向	Oncology ; Hematology
资源类型	期刊论文
条目标识符	http://119.78.100.177/qdio/handle/2XILL650/363909
作者单位	[Yi, Ming; Niu, Mengke; Li, Shiyu; Zhu, Shuangli; Chu, Qian; Wu, Kongming] Huazhong Univ Sci & Technol, Tongji Med Coll, Dept Oncol, Tongji Hosp, 1095 Jiefang Ave, Wuhan 430030, Peoples R China; [Zhang, Jing; Yan, Yongxiang; Zhou, Pengfei] Wuhan YZY Biopharma Co Ltd, C2-1,666 Gaoxin Rd, Wuhan 430075, Peoples R China; [Li, Ning; Wu, Kongming] Zhengzhou Univ, Dept Med Oncol, Affiliated Canc Hosp, Zhengzhou 450008, Peoples R China; [Li, Ning; Wu, Kongming] Henan Canc Hosp, Zhengzhou 450008, Peoples R China
推荐引用方式 GB/T 7714	Yi, Ming,Niu, Mengke,Zhang, Jing,et al. Combine and conquer: manganese synergizing anti-TGF-beta/PD-L1 bispecific antibody YM101 to overcome immunotherapy resistance in non-inflamed cancers[J],2021,14(1).
APA	Yi, Ming.,Niu, Mengke.,Zhang, Jing.,Li, Shiyu.,Zhu, Shuangli.,...&Wu, Kongming.(2021).Combine and conquer: manganese synergizing anti-TGF-beta/PD-L1 bispecific antibody YM101 to overcome immunotherapy resistance in non-inflamed cancers.JOURNAL OF HEMATOLOGY & ONCOLOGY,14(1).
MLA	Yi, Ming,et al."Combine and conquer: manganese synergizing anti-TGF-beta/PD-L1 bispecific antibody YM101 to overcome immunotherapy resistance in non-inflamed cancers".JOURNAL OF HEMATOLOGY & ONCOLOGY 14.1(2021).