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

Tat San Lau, Loucia Kit Ying Chan, Gene Chi Wai Man, Chi Hang Wong, Jacqueline Ho Sze Lee, So Fan Yim, Tak Hong Cheung, Iain A. McNeish and Joseph Kwong
Tat San Lau
1Department of Obstetrics and Gynaecology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong.
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Loucia Kit Ying Chan
1Department of Obstetrics and Gynaecology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong.
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  • ORCID record for Loucia Kit Ying Chan
Gene Chi Wai Man
2Department of Orthopaedics and Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong.
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Chi Hang Wong
3Department of Clinical Oncology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong.
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Jacqueline Ho Sze Lee
1Department of Obstetrics and Gynaecology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong.
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So Fan Yim
1Department of Obstetrics and Gynaecology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong.
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Tak Hong Cheung
1Department of Obstetrics and Gynaecology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong.
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Iain A. McNeish
4Department of Surgery & Cancer, Faculty of Medicine, Imperial College London, London, United Kingdom.
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  • ORCID record for Iain A. McNeish
Joseph Kwong
1Department of Obstetrics and Gynaecology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong.
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  • For correspondence: josephkwong@cuhk.edu.hk
DOI: 10.1158/2326-6066.CIR-19-0616 Published August 2020
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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.

Footnotes

  • Note: Supplementary data for this article are available at Cancer Immunology Research Online (http://cancerimmunolres.aacrjournals.org/).

  • Cancer Immunol Res 2020;8:1099–111

  • Received August 13, 2019.
  • Revision received February 25, 2020.
  • Accepted April 17, 2020.
  • Published first April 30, 2020.
  • ©2020 American Association for Cancer Research.
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Cancer Immunology Research: 8 (8)
August 2020
Volume 8, Issue 8
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Paclitaxel Induces Immunogenic Cell Death in Ovarian Cancer via TLR4/IKK2/SNARE-Dependent Exocytosis
Tat San Lau, Loucia Kit Ying Chan, Gene Chi Wai Man, Chi Hang Wong, Jacqueline Ho Sze Lee, So Fan Yim, Tak Hong Cheung, Iain A. McNeish and Joseph Kwong
Cancer Immunol Res August 1 2020 (8) (8) 1099-1111; DOI: 10.1158/2326-6066.CIR-19-0616

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Paclitaxel Induces Immunogenic Cell Death in Ovarian Cancer via TLR4/IKK2/SNARE-Dependent Exocytosis
Tat San Lau, Loucia Kit Ying Chan, Gene Chi Wai Man, Chi Hang Wong, Jacqueline Ho Sze Lee, So Fan Yim, Tak Hong Cheung, Iain A. McNeish and Joseph Kwong
Cancer Immunol Res August 1 2020 (8) (8) 1099-1111; DOI: 10.1158/2326-6066.CIR-19-0616
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