Abstract
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 Ser727-Stat1 (pS727-Stat1), and IFN-γ induced dephosphorylation of phospho-Tyr705-Stat3 (pY705-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 pS727-Stat1 and inhibition of pY705-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.
Highlights
Chemotherapy is considered myelo- and immunosuppressive [1], the combination of a number of chemotherapeutic regimens have been shown to enhance the anti-tumor effects of cancer vaccines and adoptive cell therapy [2,3,4,5,6,7]
We have for the first time investigated the effect of combination therapy where pancreatic cancer (PC) cells were pretreated with suboptimal concentrations of AT-101 followed by incubation with activated T cells (ATC) and armed ATC (aATC)-mediated cytotoxicity of tumor targets
EGFR through bispecific antibody (EGFRBi) armed ATCmediated apoptosis in AT-101 sensitized L3.6pl and MiaPaCa-2 cells may be facilitated by increased expression of pBad and Bax and partially through repressing Bcl-XL expression
Summary
Chemotherapy is considered myelo- and immunosuppressive [1], the combination of a number of chemotherapeutic regimens have been shown to enhance the anti-tumor effects of cancer vaccines and adoptive cell therapy [2,3,4,5,6,7]. Tumor sensitization with immunotherapy prior to chemotherapy, the ‘‘chemocentric chemoimmunotherapy’’ approach has shown profound enhancement of the cytotoxic effect of chemotherapeutic drugs [12]. While in other Phase I/II studies in solid tumors, AT-101 either as a single agent or in combination therapy failed to show clinical efficacy mainly due to dose related toxicities [20,21]. We hypothesized that combining pan-Bcl-2 inhibitor AT-101 at a suboptimal concentration with targeted activated T-cells may offer a greater treatment efficacy
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