Abstract
BackgroundTNF-related apoptosis-inducing ligand (TRAIL) is an immune effector molecule that functions as a selective anti-tumor agent. However, tumor cells, especially metastatic tumor cells often exhibit a TRAIL-resistant phenotype, which is currently a major impediment in TRAIL therapy. The aim of this study is to investigate the synergistic effect of TNFα and IFN-γ in sensitizing metastatic colon carcinoma cells to TRAIL-mediated apoptosis.Methodology/Principal FindingsThe efficacy and underlying molecular mechanism of cooperation between TNFα and IFN-γ in sensitizing metastatic colon carcinoma cells to TRAIL-mediated apoptosis were examined. The functional significance of TNFα- and IFN-γ-producing T lymphocyte immunotherapy in combination with TRAIL therapy in suppression of colon carcinoma metastasis was determined in an experimental metastasis mouse model. We observed that TNFα or IFN-γ alone exhibits minimal sensitization effects, but effectively sensitized metastatic colon carcinoma cells to TRAIL-induced apoptosis when used in combination. TNFα and IFN-γ cooperate to repress Bcl-xL expression, whereas TNFα represses Survivin expression in the metastatic colon carcinoma cells. Silencing Bcl-xL expression significantly increased the metastatic colon carcinoma cell sensitivity to TRAIL-induced apoptosis. Conversely, overexpression of Bcl-xL significantly decreased the tumor cell sensitivity to TRAIL-induced apoptosis. Furthermore, TNFα and IFN-γ also synergistically enhanced TRAIL-induced caspase-8 activation. TNFα and IFN-γ was up-regulated in activated primary and tumor-specific T cells. TRAIL was expressed in tumor-infiltrating immune cells in vivo, and in tumor-specific cytotoxic T lymphocytes (CTL) ex vivo. Consequently, TRAIL therapy in combination with TNFα/IFN-γ-producing CTL adoptive transfer immunotherapy effectively suppressed colon carcinoma metastasis in vivo.Conclusions/SignificanceTNFα and IFN-γ cooperate to overcome TRAIL resistance at least partially through enhancing caspase 8 activation and repressing Bcl-xL expression. Combined CTL immunotherapy and TRAIL therapy hold great promise for further development for the treatment of metastatic colorectal cancer.
Highlights
Recent advance in chemotherapeutic and biological agents for metastatic colorectal cancer, combined with liver resection, has dramatically increased the survival of patients with advanced colorectal cancer [1]
It has recently been shown that metastatic tumor cells often develop greater degree of TNF-related apoptosis-inducing ligand (TRAIL) resistance [34,35] and we observed that metastatic colon carcinoma cells are not sensitive to IFN-c sensitization (Fig. 1A&B)
We hypothesized that TNFa might cooperate with IFN-c to modulate TRAIL-induced apoptosis in metastatic colon carcinoma cells
Summary
Recent advance in chemotherapeutic and biological agents for metastatic colorectal cancer, combined with liver resection, has dramatically increased the survival of patients with advanced colorectal cancer [1]. Molecular analysis of large cohorts of human colorectal cancers revealed that the level of T lymphocytes and immune effector molecules in the tumor microenvironment are positively correlated with the growth, metastasis and recurrence of human colorectal tumors [5,6,7,8]. Both immune cells and immune effector molecules are potentially effective anti-tumor biologic agents. The aim of this study is to investigate the synergistic effect of TNFa and IFNc in sensitizing metastatic colon carcinoma cells to TRAIL-mediated apoptosis
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