TRAIL-Induced Apoptosis Is Preferentially Mediated via TRAIL Receptor 1 in Pancreatic Carcinoma Cells and Profoundly Enhanced by XIAP Inhibitors

Abstract

Purpose: We previously reported that small molecule X-linked inhibitor of apoptosis (XIAP) inhibitors synergize with soluble TRAIL to trigger apoptosis in pancreatic carcinoma cells. Because cancers may preferentially signal via 1 of the 2 agonistic TRAIL receptors, we investigated these receptors as a therapeutic target in pancreatic cancer in the present study.Experimental Design: We examined TRAIL receptor expression and cytotoxicity of specific monoclonal antibodies to TRAIL-R1 (HGS-ETR1, mapatumumab) or TRAIL-R2 (HGS-ETR2, lexatumumab) and of TRAIL receptor selective mutants alone and in combination with small molecule XIAP inhibitors in pancreatic cancer cell lines, in primary specimens, and in a xenotransplant model in vivo.Results: The majority of primary pancreatic carcinoma samples and all cell lines express one or both agonistic TRAIL receptors. Nine of 13 cell lines are more sensitive to mapatumumab-induced apoptosis, whereas lexatumumab requires cross-linking for maximal activity. Similarly, TRAIL-R1 selective mutants display higher cytotoxicity than TRAIL-R2 selective mutants. Small molecule XIAP inhibitors preferentially act in concert with mapatumumab to trigger caspase activation, caspase-dependent apoptosis, and suppress clonogenic survival. Also, primary cultured pancreatic carcinoma cells are more susceptible to mapatumumab than lexatumumab, which is significantly enhanced by a XIAP inhibitor. Importantly, combined treatment with mapatumumab and a XIAP inhibitor cooperates to suppress tumor growth in vivo.Conclusions: Mapatumumab exerts antitumor activity, especially in combination with XIAP inhibitors against most pancreatic carcinoma cell lines, whereas lexatumumab requires cross-linking for optimal cytotoxicity. These findings have important implications for the design of TRAIL-based protocols for pancreatic cancer. Clin Cancer Res; 16(23); 5734-49. Ó2010 AACR.

Immunoglobulin-like transcript receptors on human dermal CD14+dendritic cells act as a CD8-antagonist to control cytotoxic T cell priming

“…Indeed, the homogenous levels of CD8 displayed by blood-isolated naïve T cells suggests that dermal CD14 + DCs can specifically induce low CD8 expression or induce CD8 down-regulation. Our observation for the role of dermal CD14 + DCs in preferentially driving the polarization of naïve CD8 + T cells into type 2-cytokine-secreting cells is further supported by mouse studies demonstrating a role for dermal DCs in biasing toward Th2 responses (25,26). Similar to our previous study (7), we used DC subsets that were isolated from skin as well as their in vitro counterparts that were differentiated from CD34 + HPCs.…”

“…To analyze peptide-specific CD8 + T-cell priming, LCs and interstitial CD14 + DCs (CD14 + DCs) were generated by culturing HLA-A201 + CD34 + hematopoietic progenitor cells (HPCs) in the presence of GM-CSF, Flt3-L, and TNF-α for 9 d. In vitro-cultured CD1a + CD14 -LCs (in vitro LCs) and CD1a -CD14 + interstitial DCs (CD14 + DCs) were sorted, loaded with the HLA-A201-restricted melanoma peptide MART-1 (26)(27)(28)(29)(30)(31)(32)(33)(34)(35), and cultured with autologous naïve CD8 + T cells for up to 10 d. Consistent with experiments using DCs isolated from skin ( Fig. 1A), MART-1-specific CD8 + T cells expressed higher amounts of surface CD8 when primed by in vitro-generated LCs, compared with CD8 + T cells primed with CD14 + DCs ( Fig.…”

TRAIL-engineered pancreas-derived mesenchymal stem cells: characterization and cytotoxic effects on pancreatic cancer cells

“…30 The DRs (DR4 and DR5) are frequently expressed in cancer and transformed cells. 21,31 In the present study, the highly expressed DR5 was identified in human pancreatic adenocarcinoma (BXPC3 and ASPC1), insulinoma (HP62) and SV40 viral DNA-transformed human islet cell line (TRM6). However, human pancreatic epithelioid carcinoma cell line (PANC1) showed remarkably low expression of DRs, which is in contrast to a recent report.…”

“…However, human pancreatic epithelioid carcinoma cell line (PANC1) showed remarkably low expression of DRs, which is in contrast to a recent report. 31 These cell lines with different patterns of TRAIL receptor expression can serve as constructive tools for other TRAIL-related studies.…”

TRAIL Mediated Signaling in Pancreatic Cancer

“…Monoclonal antibodies against DR4 (HGS-ETR1, mapatumumab) or DR5 (HGS-ETR2, lexatumumab) were found to be effective when used as combination therapy in MiaPaCa2 cells. Mapatumumab efficiently induced regression of tumor growth in xenografted mice (Stadel et al, 2010). Oral administration of phenethyl isothiocyanate inhibited tumor growth of MIAPaca2 cancer cells in xenografted mice (Stan et al, 2013).…”