Preliminary mechanistic exploration of Ern1-mediated regulation of tumor immunogenicity
10.3969/j.issn.1000-484X.2024.05.001
- VernacularTitle:Ern1调控肿瘤免疫原性机制的初步探索
- Author:
Mohan LI
1
;
Lin XIA
;
Yuting MA
Author Information
1. 南京医科大学肿瘤个体化医学协同创新中心,南京 211166
- Keywords:
Unfolded protein response;
Tumor immunogenicity;
Interferon;
ER stress
- From:
Chinese Journal of Immunology
2024;40(5):897-904
- CountryChina
- Language:Chinese
-
Abstract:
Objective:To investigate whether endoplasmic reticulum transmembrane protein IRE1(encoded by Ern1)can modulate the immunogenicity and tumorigenicity of cancer cells and explore the underlying mechanism.Methods:Correlation between ERN1 expression and the overall survival of cancer patients was explored with public cancer databases.CRISPR-Cas9 technology was used to delete Ern1 in mouse tumor cell lines MCA205 and TC-1.By CCK-8,flow cytometry,ELISA,luciferase reporter systems,subcutaneous tumor models,prime-boost regimens,we analyzed impact of Ern1 on tumor cell proliferation in vitro and tumor growth in vivo,intratumoral immune cell composition,tunicamycin-induced immunogenic cell death and activation of anti-tumor effector T cells.The growth kinetics of Ern1-/-tumors was also monitored in Ifnar-/-mice.Results:ERN1 expression was found to be negatively correlated with the overall survival of cancer patients across multiple cancer types.Although Ern1 deficiency didn't affect tumor cell proliferation in vitro,it largely delayed tumor growth or caused spontaneous tumor regression in immune-competent mice.As compared to wild type counterparts,Ern1-/-tumors harbored much more neutrophils but significantly less CD4+T cells.Upon tunicamycin-induced endoplasmic reticulum stress,Ern1-/-cells were more vulnerable to cell death.Although Ern1-deficiency reduced HMGB1 release and calreticulin exposure,IFN-α/β secretion was increased,and strongly elevated type Ⅰ IFN response in tumor cells and augmented IFN-γ production by anti-tumor effector T cells.Ern1-/-tumor cells restored the tumorigenic capacity in Ifnar-/-mice.Conclusion:Ern1 defi-ciency can enhance the immunogenicity of tumor cells and inhibit tumor outgrowth by boosting endoplasmic reticulum stress-induced type Ⅰ IFN response.
