Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.
Department of Dermatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
Cell Commun Signal. 2024 Jan 30;22(1):83. doi: 10.1186/s12964-024-01470-8.
Tumor cells frequently suffer from endoplasmic reticulum (ER) stress. Previous studies have extensively elucidated the role of tumorous unfolded protein response in melanoma cells, whereas the effect on tumor immunology and the underlying mechanism remain elusive.
Bioinformatics, biochemical assays and pre-clinical mice model were employed to demonstrate the role of tumorous inositol-requiring transmembrane kinase/endoribonuclease 1α (IRE1α) in anti-tumor immunity and the underlying mechanism.
We firstly found that IRE1α signaling activation was positively associated with the feature of tumor-infiltrating lymphocytes. Then, pharmacological ER stress induction by HA15 exerted prominent anti-tumor effect in immunocompetent mice and was highly dependent on CD8T cells, paralleled with the reshape of immune cells in tumor microenvironment via tumorous IRE1α-XBP1 signal. Subsequently, tumorous IRE1α facilitated the expression and secretion of multiple chemokines and cytokines via XBP1-NF-κB axis, leading to increased infiltration and anti-tumor capacity of CD8T cells. Ultimately, pharmacological induction of tumorous ER stress by HA15 brought potentiated therapeutic effect along with anti-PD-1 antibody on melanoma in vivo.
Tumorous IRE1α facilitates CD8T cells-dependent anti-tumor immunity and improves immunotherapy efficacy by regulating chemokines and cytokines via XBP1-NF-κB axis. The combination of ER stress inducer and anti-PD-1 antibody could be promising for increasing the efficacy of melanoma immunotherapy.
肿瘤细胞经常遭受内质网（ER）应激。先前的研究广泛阐明了肿瘤 unfolded 蛋白反应在黑色素瘤细胞中的作用，而其对肿瘤免疫学的影响和潜在机制仍不清楚。
采用生物信息学、生化测定和临床前小鼠模型来证明肿瘤内质网跨膜激酶/内切核酸酶 1α（IRE1α）在抗肿瘤免疫中的作用及其潜在机制。
我们首先发现 IRE1α 信号激活与肿瘤浸润淋巴细胞的特征呈正相关。然后，HA15 诱导的内质网应激通过激活肿瘤内质网跨膜激酶/内切核酸酶 1α（IRE1α）-X 盒结合蛋白 1（XBP1）信号重塑肿瘤微环境中的免疫细胞，在免疫功能正常的小鼠中发挥显著的抗肿瘤作用，且高度依赖 CD8T 细胞。随后，肿瘤内质网跨膜激酶/内切核酸酶 1α（IRE1α）通过 XBP1-NF-κB 轴促进多种趋化因子和细胞因子的表达和分泌，导致 CD8T 细胞浸润增加和抗肿瘤能力增强。最终，HA15 通过诱导肿瘤内质网应激，增强了体内黑色素瘤的治疗效果，并与抗 PD-1 抗体产生协同作用。
肿瘤内质网跨膜激酶/内切核酸酶 1α（IRE1α）通过 XBP1-NF-κB 轴调节趋化因子和细胞因子，促进 CD8T 细胞依赖性抗肿瘤免疫，并提高免疫治疗疗效。内质网应激诱导剂与抗 PD-1 抗体联合使用可能有望提高黑色素瘤免疫治疗的疗效。
