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Immunodominant AH1 antigen-deficient necroptotic, but not apoptotic, murine cancer cells induce antitumor protection

Tania Love Aaes (UGent) , Hanne Verschuere (UGent) , Agnieszka Kaczmarek (UGent) , Liesbeth Heyndrickx (UGent) , Bartosz Wiernicki (UGent) , Iris Delrue (UGent) , Bram De Craene (UGent) , Joachim Taminau (UGent) , Tinneke Delvaeye (UGent) , Mathieu Bertrand (UGent) , et al.
(2020) JOURNAL OF IMMUNOLOGY. 204(4). p.775-787
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Abstract
Immunogenic cell death (ICD) occurs when a dying cell releases cytokines and damage-associated molecular patterns, acting as adjuvants, and expresses Ags that induce a specific antitumor immune response. ICD is studied mainly in the context of regulated cell death pathways, especially caspase-mediated apoptosis marked by endoplasmic reticulum stress and calreticulin exposure and, more recently, also in relation to receptor-interacting protein kinase-driven necroptosis, whereas unregulated cell death like accidental necrosis is nonimmunogenic. Importantly, the murine cancer cell lines used in ICD studies often express virally derived peptides that are recognized by the immune system as tumor-associated Ags. However, it is unknown how different cell death pathways may affect neoepitope cross-presentation and Ag recognition of cancer cells. We used a prophylactic tumor vaccination model and observed that both apoptotic and necroptotic colon carcinoma CT26 cells efficiently immunized mice against challenge with a breast cancer cell line that expresses the same immunodominant tumor Ag, AH1, but only necroptotic CT26 cells would mount an immune response against CT26-specific neoepitopes. By CRISPR/Cas9 genome editing, we knocked out AH1 and saw that only necroptotic CT26 cells were still able to protect mice against tumor challenge. Hence, in this study, we show that endogenous AH1 tumor Ag expression can mask the strength of immunogenicity induced by different cell death pathways and that upon knockout of AH1, necroptosis was more immunogenic than apoptosis in a prophylactic tumor vaccination model. This work highlights necroptosis as a possible preferred ICD form over apoptosis in the treatment of cancer.
Keywords
IMMUNE-RESPONSES, DEATH DOMAIN, CHEMOTHERAPEUTIC-AGENTS, CALRETICULIN, EXPOSURE, TUMOR-GROWTH, IN-VIVO, PROTEIN, IMMUNOGENICITY, MOUSE, IMMUNIZATION

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MLA
Aaes, Tania Love, et al. “Immunodominant AH1 Antigen-Deficient Necroptotic, but Not Apoptotic, Murine Cancer Cells Induce Antitumor Protection.” JOURNAL OF IMMUNOLOGY, vol. 204, no. 4, 2020, pp. 775–87.
APA
Aaes, T. L., Verschuere, H., Kaczmarek, A., Heyndrickx, L., Wiernicki, B., Delrue, I., … Vandenabeele, P. (2020). Immunodominant AH1 antigen-deficient necroptotic, but not apoptotic, murine cancer cells induce antitumor protection. JOURNAL OF IMMUNOLOGY, 204(4), 775–787.
Chicago author-date
Aaes, Tania Love, Hanne Verschuere, Agnieszka Kaczmarek, Liesbeth Heyndrickx, Bartosz Wiernicki, Iris Delrue, Bram De Craene, et al. 2020. “Immunodominant AH1 Antigen-Deficient Necroptotic, but Not Apoptotic, Murine Cancer Cells Induce Antitumor Protection.” JOURNAL OF IMMUNOLOGY 204 (4): 775–87.
Chicago author-date (all authors)
Aaes, Tania Love, Hanne Verschuere, Agnieszka Kaczmarek, Liesbeth Heyndrickx, Bartosz Wiernicki, Iris Delrue, Bram De Craene, Joachim Taminau, Tinneke Delvaeye, Mathieu Bertrand, Wim Declercq, Geert Berx, Dmitri Krysko, Sandy Adjemian Catani, and Peter Vandenabeele. 2020. “Immunodominant AH1 Antigen-Deficient Necroptotic, but Not Apoptotic, Murine Cancer Cells Induce Antitumor Protection.” JOURNAL OF IMMUNOLOGY 204 (4): 775–787.
Vancouver
1.
Aaes TL, Verschuere H, Kaczmarek A, Heyndrickx L, Wiernicki B, Delrue I, et al. Immunodominant AH1 antigen-deficient necroptotic, but not apoptotic, murine cancer cells induce antitumor protection. JOURNAL OF IMMUNOLOGY. 2020;204(4):775–87.
IEEE
[1]
T. L. Aaes et al., “Immunodominant AH1 antigen-deficient necroptotic, but not apoptotic, murine cancer cells induce antitumor protection,” JOURNAL OF IMMUNOLOGY, vol. 204, no. 4, pp. 775–787, 2020.
@article{8650503,
  abstract     = {{Immunogenic cell death (ICD) occurs when a dying cell releases cytokines and damage-associated molecular patterns, acting as adjuvants, and expresses Ags that induce a specific antitumor immune response. ICD is studied mainly in the context of regulated cell death pathways, especially caspase-mediated apoptosis marked by endoplasmic reticulum stress and calreticulin exposure and, more recently, also in relation to receptor-interacting protein kinase-driven necroptosis, whereas unregulated cell death like accidental necrosis is nonimmunogenic. Importantly, the murine cancer cell lines used in ICD studies often express virally derived peptides that are recognized by the immune system as tumor-associated Ags. However, it is unknown how different cell death pathways may affect neoepitope cross-presentation and Ag recognition of cancer cells. We used a prophylactic tumor vaccination model and observed that both apoptotic and necroptotic colon carcinoma CT26 cells efficiently immunized mice against challenge with a breast cancer cell line that expresses the same immunodominant tumor Ag, AH1, but only necroptotic CT26 cells would mount an immune response against CT26-specific neoepitopes. By CRISPR/Cas9 genome editing, we knocked out AH1 and saw that only necroptotic CT26 cells were still able to protect mice against tumor challenge. Hence, in this study, we show that endogenous AH1 tumor Ag expression can mask the strength of immunogenicity induced by different cell death pathways and that upon knockout of AH1, necroptosis was more immunogenic than apoptosis in a prophylactic tumor vaccination model. This work highlights necroptosis as a possible preferred ICD form over apoptosis in the treatment of cancer.}},
  author       = {{Aaes, Tania Love and Verschuere, Hanne and Kaczmarek, Agnieszka and Heyndrickx, Liesbeth and Wiernicki, Bartosz and Delrue, Iris and De Craene, Bram and Taminau, Joachim and Delvaeye, Tinneke and Bertrand, Mathieu and Declercq, Wim and Berx, Geert and Krysko, Dmitri and Adjemian Catani, Sandy and Vandenabeele, Peter}},
  issn         = {{0022-1767}},
  journal      = {{JOURNAL OF IMMUNOLOGY}},
  keywords     = {{IMMUNE-RESPONSES,DEATH DOMAIN,CHEMOTHERAPEUTIC-AGENTS,CALRETICULIN,EXPOSURE,TUMOR-GROWTH,IN-VIVO,PROTEIN,IMMUNOGENICITY,MOUSE,IMMUNIZATION}},
  language     = {{eng}},
  number       = {{4}},
  pages        = {{775--787}},
  title        = {{Immunodominant AH1 antigen-deficient necroptotic, but not apoptotic, murine cancer cells induce antitumor protection}},
  url          = {{http://dx.doi.org/10.4049/jimmunol.1900072}},
  volume       = {{204}},
  year         = {{2020}},
}

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