Caspase-1 from Human Myeloid Derived Suppressor Cells Can Promote T-cell independent Tumor Proliferation
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ABSTRACT:
PROVIDER: PRJNA447932 | ENA |
REPOSITORIES: ENA
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Project description:Immunosuppressive myeloid-derived suppressive cells (MDSCs) are characterized by their phenotypic and functional heterogeneity. To better define their T cell-independent functions within the tumor, sorted monocytic CD14+CD11b+HLA-DRlow/- MDSCs (mMDSCs) from squamous cell carcinoma patients showed upregulated caspase-1 activity, that was associated with increased IL1b and IL18 expression. In vitro studies demonstrated that mMDSCs promoted caspase-1-dependent proliferation of multiple squamous carcinoma cell lines in both human and murine systems. In vivo, growth rates of B16, MOC1, and Panc02 were significantly blunted in chimeric mice adoptively transferred with caspase-1 null bone marrow cells under T cell-depleted conditions. Adoptive transfer of wildtype Gr-1+CD11b+ MDSCs from tumor-bearing mice reversed this antitumor response, whereas caspase-1 inhibiting thalidomide-treated MDSCs phenocopied the antitumor response found in caspase-1 null mice. We further hypothesized that MDSC caspase-1 activity could promote tumor intrinsic MyD88-dependent carcinogenesis. In mice with wildtype caspase-1, MyD88-silenced tumors displayed reduced growth rate, but in chimeric mice with caspase-1 null bone marrow cells, MyD88-silenced tumors did not display differential tumor growth rate. When we queried the TCGA database, we found that caspase-1 expression is correlated with overall survival in squamous cell carcinoma patients. Taken together, our findings demonstrated that caspase-1 in MDSCs is a direct T cell-independent mediator of tumor proliferation.
2021-03-02 | GSE112481 | GEO
Project description:Death ligands, including FAS ligand (FASL) and tumor necrosis factor (TNF), trigger apoptosis by promoting caspase-8 dimerization and activation. Impaired FAS signaling causes unconventional lymphocytes to accumulate, resulting in lymphadenopathy. Although autoprocessing of caspase-8 is considered important for apoptosis, autoprocessing-deficient Casp8 D387A/D387A mice do not develop lymphadenopathy. We show that this is because heterodimers of caspase-8 D387A and cFLIP, besides suppressing MLKL-driven necroptosis, can also induce apoptosis. Interestingly, caspase-8 D387A elicited MLKL- and caspase-1-independent intestinal atrophy and perinatal lethality in mice lacking cFLIP. Caspase-8 D387A interacted with FADD and RIPK1 in the intestine, where there was aberrant cleavage of N4BP1 and caspase-3, plus enhanced NF-κB signaling. Eliminating FADD, the adaptor protein that promotes caspase-8 oligomerization, prevented this perinatal lethality. Collectively, our results suggest that cFLIP forms heterodimers with caspase-8 D387A to promote apoptosis in some contexts, while limiting the activity of caspase-8 D387A homodimers in others.
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Project description:Immunosuppressive myeloid-derived suppressive cells (MDSCs) are characterized by their phenotypic and functional heterogeneity. To better define their T cell-independent functions within the tumor, sorted monocytic CD14+CD11b+HLA-DRlow/- MDSCs (mMDSC) from squamous cell carcinoma patients showed upregulated caspase-1 activity, which was associated with increased IL1β and IL18 expression. In vitro studies demonstrated that mMDSCs promoted caspase-1-dependent proliferation of multiple squamous carcinoma cell lines in both human and murine systems. In vivo, growth rates of B16, MOC1, and Panc02 were significantly blunted in chimeric mice adoptively transferred with caspase-1 null bone marrow cells under T cell-depleted conditions. Adoptive transfer of wild-type Gr-1+CD11b+ MDSCs from tumor-bearing mice reversed this antitumor response, whereas caspase-1 inhibiting thalidomide-treated MDSCs phenocopied the antitumor response found in caspase-1 null mice. We further hypothesized that MDSC caspase-1 activity could promote tumor-intrinsic MyD88-dependent carcinogenesis. In mice with wild-type caspase-1, MyD88-silenced tumors displayed reduced growth rate, but in chimeric mice with caspase-1 null bone marrow cells, MyD88-silenced tumors did not display differential tumor growth rate. When we queried the TCGA database, we found that caspase-1 expression is correlated with overall survival in squamous cell carcinoma patients. Taken together, our findings demonstrated that caspase-1 in MDSCs is a direct T cell-independent mediator of tumor proliferation. Cancer Immunol Res; 6(5); 566-77. ©2018 AACR.
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