Paclitaxel Induces Immunogenic Cell Death in Ovarian Cancer via TLR4/IKK2/SNARE-Dependent Exocytosis

Lau, Tat San; Chan, Loucia Kit Ying; Man, Gene Chi Wai; Wong, Chi Hang; Lee, Jacqueline Ho Sze; Yim, So Fan; Cheung, Tak Hong; McNeish, Iain A.; Kwong, Joseph

Abstract

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.

Citation

Lau, T. S., Chan, L. K. Y., Man, G. C. W., Wong, C. H., Lee, J. H. S., Yim, S. F., Cheung, T. H., McNeish, I. A., & Kwong, J. (2020). Paclitaxel Induces Immunogenic Cell Death in Ovarian Cancer via TLR4/IKK2/SNARE-Dependent Exocytosis. Cancer Immunology Research, 8(8), 1099-1111. https://doi.org/10.1158/2326-6066.CIR-19-0616

• Journal Article Type: Article
• Acceptance Date: Apr 17, 2020
• Publication Date: 2020-08
• Deposit Date: Jun 26, 2023
• Journal: CANCER IMMUNOLOGY RESEARCH
• Print ISSN: 2326-6066
• Electronic ISSN: 2326-6074
• Publisher: American Association for Cancer Research
• Peer Reviewed: Peer Reviewed
• Volume: 8
• Issue: 8
• Pages: 1099-1111
• DOI: https://doi.org/10.1158/2326-6066.CIR-19-0616
• Public URL: https://keele-repository.worktribe.com/output/506924