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

• DOI: 10.1158/2326-6066.c.6548113.v1
• Publication Date: 2023-04-04T20:02:13Z
• Authors: Qi Zeng; Juan Fu; Michael Korrer; Mikhail Gorbounov; Peter J. Murray; Drew Pardoll; David L. Masica; Young J. Kim

<div>Abstract<p>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^low/– MDSCs (mMDSC) from squamous cell carcinoma patients showed upregulated caspase-1 activity, which was associated with increased IL1β and IL18 expression. <i>In vitro</i> studies demonstrated that mMDSCs promoted caspase-1–dependent proliferation of multiple squamous carcinoma cell lines in both human and murine systems. <i>In vivo</i>, 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. <i>Cancer Immunol Res; 6(5); 566–77. ©2018 AACR</i>.</p></div>