Caspase-1 from Human Myeloid-Derived Suppressor Cells Can Promote T Cell-Independent Tumor Proliferation

• Published in: Cancer immunology research 2018-05, Vol.6 (5), p.566-577
• Main Authors: Zeng, Qi, Fu, Juan, Korrer, Michael, Gorbounov, Mikhail, Murray, Peter J, Pardoll, Drew, Masica, David L, Kim, Young J
• Format: Article
• Language: English
• Subjects: Adoptive Transfer; Animals; Caspase 1 - metabolism; Caspase 1 - physiology; Cell Proliferation; Cells, Cultured; Humans; Mice; Mice, Inbred C57BL; Mice, Knockout; Myeloid-Derived Suppressor Cells - metabolism; Myeloid-Derived Suppressor Cells - pathology; Myeloid-Derived Suppressor Cells - transplantation; Neoplasms - immunology; Neoplasms - metabolism; Neoplasms - pathology; Neoplasms - therapy; T-Lymphocytes - physiology
• ISSN: 2326-6066; 2326-6074
• DOI: 10.1158/2326-6066.CIR-17-0543

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-DR MDSCs (mMDSC) from squamous cell carcinoma patients showed upregulated caspase-1 activity, which was associated with increased IL1β and IL18 expression. studies demonstrated that mMDSCs promoted caspase-1-dependent proliferation of multiple squamous carcinoma cell lines in both human and murine systems. , 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. .