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Proapoptotic and antiapoptotic proteins of the Bcl-2 family regulate sensitivity of pancreatic cancer cells toward gemcitabine and T-cell-mediated cytotoxicity.
J. Immunother. 38, 116-126 (2015)
Sensitivity of carcinoma cells towards gemcitabine (Gem) has been linked to mitochondrial apoptotic proteins. Recently, we described synergistic efficacy of Gem-based chemoimmunotherapy and a dendritic cell (DC) tumor vaccine in a murine pancreatic carcinoma model. Here, we investigated the role of the mitochondrial proteins Bcl-2, Bcl-xL, and Bax for sensitization of pancreatic carcinoma cells toward T-cell-mediated cytotoxicity alone and in combination with Gem. Bcl-2 expression was silenced by siRNA in Panc02 pancreatic cancer cells expressing the model antigen ovalbumin (PancOVA). Tumor cells were treated with Gem and/or siRNA, and cytotoxicity induced by OVA-specific cytotoxic T lymphocytes (CTL) from OT-1 mice was assessed. Gem-induced and T-cell-induced cytotoxicity was also studied in human Colo357 pancreatic cancer cell lines overexpressing Bax or Bcl-xL. Apoptosis induction by Fas-activating antibody was measured by Annexin V staining. The in vivo capacity of Bcl-2 siRNA to augment CTL efficacy induced by DC vaccinations was assessed in C57BL/6 mice bearing PancOVA tumors. PancOVA cells treated with Bcl-2 siRNA were sensitized towards both Gem and T-cell-mediated killing; combination therapy exhibited an additive effect. Bax overexpression sensitized Colo357 cells to both Gem-mediated and T-cell-mediated cytotoxicity, whereas Bcl-xL overexpression was inhibitory. Combining Bcl-2 silencing with DC therapy improved tumor control in the PancOVA model in vivo without affecting the number of tumor-reactive CTL. In conclusion, expression of Bcl-2, Bcl-xL, and Bax in pancreatic tumor cells determines sensitivity towards both Gem-mediated and CTL-mediated toxicity. Bcl-2 silencing could be exploited therapeutically in tumor vaccine approaches.
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Publikationstyp
Artikel: Journalartikel
Dokumenttyp
Wissenschaftlicher Artikel
Schlagwörter
Bcl-2 ; Chemotherapy ; Dendritic Cells ; Gemcitabine ; Mitochondrial Proteins ; Pancreatic Carcinoma ; Sirna ; Vaccination; Pulsed Dendritic Cells; Granzyme-b; Adenocarcinoma Cells; Prostate Carcinoma; Positive Selection; Caspase Activation; Signaling Pathway; Induced Apoptosis; Human-melanoma; Solid Tumors
ISSN (print) / ISBN
1524-9557
e-ISSN
1537-4513
Zeitschrift
Journal of Immunotherapy
Quellenangaben
Band: 38,
Heft: 3,
Seiten: 116-126
Verlag
Lippincott Williams & Wilkins
Verlagsort
Philadelphia
Nichtpatentliteratur
Publikationen
Begutachtungsstatus
Peer reviewed
Institut(e)
Institute of Molecular Immunology (IMI)