Paclitaxel induces immunogenic cell death in ovarian cancer via TLR4/IKK2/SNARE-dependent exocytosis
| Autor: | Tat San Lau, Chi Hang Wong, Loucia K.Y. Chan, Joseph Kwong, Tak Hong Cheung, So Fan Yim, Gene Chi Wai Man, Iain A. McNeish, Jacqueline Ho Sze Lee |
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| Přispěvatelé: | Imperial College Healthcare NHS Trust- BRC Funding, Cancer Research UK, Ovarian Cancer Action |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Adult Cancer Research Paclitaxel medicine.medical_treatment Immunology Cell Antineoplastic Agents Immunogenic Cell Death Cancer Vaccines Exocytosis 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine Cell Line Tumor Medicine Animals Humans 1112 Oncology and Carcinogenesis Aged Ovarian Neoplasms Chemotherapy business.industry Kinase Middle Aged medicine.disease I-kappa B Kinase Mice Inbred C57BL Toll-Like Receptor 4 Disease Models Animal 030104 developmental biology medicine.anatomical_structure chemistry 1107 Immunology 030220 oncology & carcinogenesis Cancer cell Cancer research Immunogenic cell death Female Signal transduction 1115 Pharmacology and Pharmaceutical Sciences business Ovarian cancer SNARE Proteins Signal Transduction |
| Popis: | Emerging evidence shows that the efficacy of chemotherapeutic drugs is reliant on their capability to induce immunogenic cell death (ICD), thus transforming dying tumor cells into antitumor vaccines. We wanted to uncover potential therapeutic strategies that target ovarian cancer by having a better understanding of the standard-of-care chemotherapy treatment. Here, we showed in ovarian cancer that paclitaxel induced ICD-associated damage-associated molecular patterns (DAMP, such as CALR exposure, ATP secretion, and HMGB1 release) in vitro and elicited significant antitumor responses in tumor vaccination assays in vivo. Paclitaxel-induced TLR4 signaling was essential to the release of DAMPs, which led to the activation of NF-κB–mediated CCL2 transcription and IkappaB kinase 2–mediated SNARE-dependent vesicle exocytosis, thus exposing CALR on the cell surface. Paclitaxel induced endoplasmic reticulum stress, which triggered protein kinase R–like ER kinase activation and eukaryotic translation initiation factor 2α phosphorylation independent of TLR4. Paclitaxel chemotherapy induced T-cell infiltration in ovarian tumors of the responsive patients; CALR expression in primary ovarian tumors also correlated with patients' survival and patient response to chemotherapy. These findings suggest that the effectiveness of paclitaxel relied upon the activation of antitumor immunity through ICD via TLR4 and highlighted the importance of CALR expression in cancer cells as an indicator of response to paclitaxel chemotherapy in ovarian cancer. |
| Databáze: | OpenAIRE |
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