Pancreatic cancer is a deadly disease and has the worst prognosis among almost all
cancers and is in dire need of new and improved therapeutic strategies. Conditioning of
tumor cells with chemotherapeutic
drug has been shown to enhance the anti-
tumor effects of
cancer vaccines and adoptive
cell therapy. In this study, we investigated the immunomodulatory effects of pan-Bcl-2 inhibitor
AT-101 on
pancreatic cancer (PC) cell cytotoxicity by activated T cells (ATC). The effects of
AT-101 on cytotoxicity, early apoptosis, and
Granzyme B (GrzB) and IFN-γ signaling pathways were evaluated during EGFR bispecific antibody armed ATC (aATC)-mediated killing of L3.6pl and MiaPaCa-2 PC cells pre-sensitized with
AT-101. We found that pretreatment of
tumor cells with
AT-101 enhanced susceptibility of L3.6pl and MiaPaCa-2
tumor cells to ATC and aATC-mediated cytotoxicity, which was in part mediated via enhanced release of cytolytic granule GrzB from ATC and aATC. AT-101-sensitized L3.6pl cells showed up-regulation of IFN-γ-mediated induction in the phosphorylation of Ser(727)-Stat1 (pS(727)-Stat1), and IFN-γ induced dephosphorylation of phospho-Tyr(705)-Stat3 (pY(705)-Stat3). Priming (conditioning) of PC cells with
AT-101 can significantly enhance the anti-
tumor activity of EGFRBi armed ATC through increased IFN-γ induced activation of pS(727)-Stat1 and inhibition of pY(705)-Stat3 phosphorylation, and resulting in increased ratio of pro-apoptotic to
anti-apoptotic proteins. Our results verify enhanced cytotoxicity after a novel
chemotherapy conditioning strategy against PC that warrants further in vivo and clinical investigations.