LSD1 缺失降低胃癌细胞外泌体 PD-L1 并恢复 T 细胞反应。
LSD1 deletion decreases exosomal PD-L1 and restores T-cell response in gastric cancer.
机构信息
Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, Institute of Drug Discovery and Development, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Henan, 450052, Zhengzhou, China.
State Key Laboratory of Esophageal Cancer Prevention & Treatment, Academy of Medical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan, China.
出版信息
Mol Cancer. 2022 Mar 16;21(1):75. doi: 10.1186/s12943-022-01557-1.
BACKGROUND
Histone lysine-specific demethylase 1 (LSD1) expression has been shown to be significantly elevated in gastric cancer (GC) and may be associated with the proliferation and metastasis of GC. It has been reported that LSD1 repressed tumor immunity through programmed cell death 1 ligand 1 (PD-L1) in melanoma and breast cancer. The role of LSD1 in the immune microenvironment of GC is unknown.
METHODS
Expression LSD1 and PD-L1 in GC patients was analyzed by immunohistochemical (IHC) and Western blotting. Exosomes were isolated from the culture medium of GC cells using an ultracentrifugation method and characterized by transmission electronic microscopy (TEM), nanoparticle tracking analysis (NTA), sucrose gradient centrifugation, and Western blotting. The role of exosomal PD-L1 in T-cell dysfunction was assessed by flow cytometry, T-cell killing and enzyme-linked immunosorbent assay (ELISA).
RESULTS
Through in vivo exploration, mouse forestomach carcinoma (MFC) cells with LSD1 knockout (KO) showed significantly slow growth in 615 mice than T-cell-deficient BALB/c nude mice. Meanwhile, in GC specimens, expression of LSD1 was negatively correlated with that of CD8 and positively correlated with that of PD-L1. Further study showed that LSD1 inhibited the response of T cells in the microenvironment of GC by inducing the accumulation of PD-L1 in exosomes, while the membrane PD-L1 stayed constant in GC cells. Using exosomes as vehicles, LSD1 also obstructed T-cell response of other cancer cells while LSD1 deletion rescued T-cell function. It was found that while relying on the existence of LSD1 in donor cells, exosomes can regulate MFC cells proliferation with distinct roles depending on exosomal PD-L1-mediated T-cell immunity in vivo.
CONCLUSION
LSD1 deletion decreases exosomal PD-L1 and restores T-cell response in GC; this finding indicates a new mechanism with which LSD1 may regulate cancer immunity in GC and provides a new target for immunotherapy against GC.
背景
组蛋白赖氨酸特异性去甲基化酶 1（LSD1）在胃癌（GC）中的表达显著升高，可能与 GC 的增殖和转移有关。据报道，LSD1 通过程序性细胞死亡配体 1（PD-L1）在黑色素瘤和乳腺癌中抑制肿瘤免疫。LSD1 在 GC 免疫微环境中的作用尚不清楚。
方法
通过免疫组织化学（IHC）和 Western blot 分析 GC 患者 LSD1 和 PD-L1 的表达。使用超速离心法从 GC 细胞的培养基中分离外泌体，并通过透射电子显微镜（TEM）、纳米颗粒跟踪分析（NTA）、蔗糖梯度离心和 Western blot 进行表征。通过流式细胞术、T 细胞杀伤和酶联免疫吸附试验（ELISA）评估外泌体 PD-L1 在 T 细胞功能障碍中的作用。
结果
通过体内探索，LSD1 敲除（KO）的小鼠前胃腺癌（MFC）细胞在 615 只 T 细胞缺陷 BALB/c 裸鼠中的生长速度明显比 T 细胞缺陷 BALB/c 裸鼠慢。同时，在 GC 标本中，LSD1 的表达与 CD8 的表达呈负相关，与 PD-L1 的表达呈正相关。进一步研究表明，LSD1 通过诱导 PD-L1 在 exosomes 中的积累来抑制 GC 微环境中 T 细胞的反应，而 GC 细胞中的膜 PD-L1 保持不变。利用 exosomes 作为载体，LSD1 还可以阻止其他癌细胞的 T 细胞反应，而 LSD1 缺失则可以恢复 T 细胞功能。结果发现，LSD1 缺失可降低 exosomal PD-L1 并恢复 GC 中的 T 细胞反应；这一发现表明，LSD1 可能通过调节 GC 中的癌症免疫来发挥新的作用，并为 GC 的免疫治疗提供了新的靶点。
结论
LSD1 缺失减少了 exosomal PD-L1，并恢复了 GC 中的 T 细胞反应；这一发现表明，LSD1 可能通过调节 GC 中的癌症免疫来发挥新的作用，并为 GC 的免疫治疗提供了新的靶点。
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