PGE2 Released by Pancreatic Cancer Cells Undergoing ER Stress Transfers the Stress to DCs Impairing Their Immune Function.

免疫系统 癌症研究 胰腺癌 免疫学 细胞凋亡 肿瘤微环境 细胞毒性T细胞 医学 癌症 CD8型 炎症 免疫监视 生物 T细胞 细胞因子 肿瘤坏死因子α
作者
Maria Saveria Gilardini Montani,Rossella Benedetti,Silvia Piconese,Fabio M. Pulcinelli,Anna Maria Timperio,Maria Anele Romeo,Laura Masuelli,Maurizio Mattei,Roberto Bei,Gabriella D'Orazi,Mara Cirone
出处
期刊:Molecular Cancer Therapeutics [American Association for Cancer Research]
卷期号:20 (5): 934-945 被引量:5
标识
DOI:10.1158/1535-7163.mct-20-0699
摘要

This study shows that pancreatic cancer cells undergoing cell death by valproic acid (VPA) treatment activated dendritic cells (DCs) more efficiently than those treated with trichostatin A (TSA), as demonstrated by CD86 and CD80 surface expression. Surprisingly though, DCs cultured in the presence of supernatant derived from VPA-treated cancer cells showed a reduced allostimulatory capacity and an increased release of IL10 and IL8 cytokines in comparison with those exposed to TSA-treated cell culture supernatant. Searching for molecular mechanisms leading to such differences, we found that VPA treatment dysregulated choline metabolism and triggered a stronger endoplasmic reticulum (ER) stress in pancreatic cancer cells than TSA, upregulating CCAAT/enhancer-binding protein homologous protein, and activated cyclooxygenase-2, thus promoting the release of prostaglandin (PG) E2. Interestingly, dysfunctional DCs cultured in the presence of VPA-treated cells culture supernatant showed a higher level of intracellular reactive oxygen species, 4-hydroxy-trans-2-nonenal protein adducts, and ER stress, as evidenced by the upregulation of spliced X-box binding protein 1 (XBP1s), effects that were reduced when DCs were exposed to supernatant of cancer cells treated with Celecoxib before VPA. Celecoxib prevented PGE2 release, restoring the function of DCs exposed to VPA-treated cells culture supernatant, and a similar effect was obtained by silencing XBP1s in DCs treated with VPA-treated cells culture supernatant. These results suggest that PGE2 could be one of the yet unidentified factors able to transfer the stress from cancer cells to DCs, resulting in an impairment of their function.

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