To clarify the role of IL-1β on the intratumoral activities of polymorphonuclear (PMN) and monocytic (M) MDSCs, Tannenbaum et al. studied intratumoral MDSC accumulation and gene expression in parental and IL-1β-transfected CT26 tumors. IL-1β-transfected CT26 expressed high G-CSF and multiple CXC chemokines and trafficking molecules, resulting in enhanced peripheral expansion and intratumoral accumulation of angiogenic and immunosuppressive PMN-MDSCs, with decreased numbers of M-MDSCs. Data from human RCC patients and TCGA showed a significant correlation between high CXCL1 and worse survival.
Contributed by Katherine Turner
Myeloid-derived suppressor cells (MDSCs) are induced by and accumulate within many histologically distinct solid tumors, where they promote disease by secreting angiogenic and immunosuppressive molecules. Although IL1beta can drive the generation, accumulation, and functional capacity of MDSCs, the specific IL1beta-induced inflammatory mediators contributing to these activities remain incompletely defined. Here, we identified IL1beta-induced molecules that expand, mobilize, and modulate the accumulation and angiogenic and immunosuppressive potencies of polymorphonuclear (PMN)-MDSCs. Unlike parental CT26 tumors, which recruited primarily monocytic (M)-MDSCs by constitutively expressing GM-CSF- and CCR2-directed chemokines, IL1beta-transfected CT26 produced higher G-CSF, multiple CXC chemokines, and vascular adhesion molecules required for mediating infiltration of PMN-MDSCs with increased angiogenic and immunosuppressive properties. Conversely, CT26 tumors transfected with IL1beta-inducible molecules could mobilize PMN-MDSCs, but because they lacked the ability to upregulate IL1beta-inducible CXCR2-directed chemokines or vascular adhesion molecules, the PMN-MDSCs could not infiltrate tumors. IL1beta-expressing CT26 increased angiogenic and immunosuppressive factors of tumor-infiltrating MDSCs, as did CT26 tumors individually transfected with G-CSF, Bv8, CXCL1, or CXCL5, demonstrating that mediators downstream of IL1beta could also modulate MDSC functional activity. Translational relevance was indicated by the finding that the same growth factors, cytokines, chemokines, and adhesion molecules responsible for the mobilization and recruitment of PMN-MDSCs into inflammatory CT26 murine tumors were also coordinately upregulated with increasing IL1beta expression in human renal cell carcinoma tumors. These studies demonstrated that IL1beta stimulated the components of a multifaceted inflammatory program that produces, mobilizes, chemoattracts, activates, and mediates the infiltration of PMN-MDSCs into inflammatory tumors to promote tumor progression.