Mediators of Inflammation-Driven Expansion, Trafficking, and Function of Tumor-Infiltrating MDSCs

Abstract

Myeloid-derived suppressor cells (MDSC) are induced by and accumulate within many histologically distinct solid tumors, where they promote disease by secreting angiogenic and immunosuppressive molecules. Although IL1b can drive the generation, accumulation, and functional capacity of MDSCs, the specific IL1b-induced inflammatory mediators contributing to these activities remain incompletely defined. Here, we identified IL1b-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, IL1btransfected 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 IL1b-inducible molecules could mobilize PMN-MDSCs, but because they lacked the ability to upregulate IL1b-inducible CXCR2-directed chemokines or vascular adhesion molecules, additional PMN-MDSCs could not infiltrate tumors. IL1b-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 IL1b 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 IL1b expression in human renal cell carcinoma tumors. These studies demonstrated that IL1b 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.

Obesity diminishes response to PD-1-based immunotherapies in renal cancer

“…Treatment-naive DIO mice had increased intratumoral concentrations of the MDSC-related proteins GM-CSF, IL-1β, CXCL1 and CCL2 6 41–43 at day 15, relative to lean mice ( figure 7C ). IL-1β is a known driver of MDSC generation, accumulation and suppressive capacity, 44 45 and was decreased at the gene expression level in both lean and DIO responder mice ( figure 5B ). Investigating the IL-1β pathway is clinically relevant, as high intratumoral IL-1β gene expression is an unfavorable prognostic in renal cancer patients (p<0.001, thehumanproteinatlas.org) and elevated IL-1β in human renal tumors is associated with increased MDSC accumulation.…”

CXCL8 Associated Dendritic Cell Activation Marker Expression and Recruitment as Indicators of Favorable Outcomes in Colorectal Cancer

“…Different immune behaviors found in CT26 and MC38 colon cancer model was mainly caused by higher immune infiltration in CT26 than MC38 (23). CT26 model also provided CXCR2 dependent mediated the trafficking and function of tumor-infiltrating immune cells in the TME (24). Taken together, these results indicated that targeting CXCR2 can promote tumor growth in vivo but had little or no direct effect on the proliferation of CRC tumor cells in vitro, which may be attributed to the difference between extracellular factors and intracellular factors in the tumor process.…”

Targeting Myeloid-Derived Suppressor Cells for Premetastatic Niche Disruption After Tumor Resection

“…IL-1β enhances the generation, accumulation, and activity of MDSCs by activating IL-1β-inducible growth factors, cytokines, CXCR2-directed chemokines, and adhesion molecules that are associated with G-MDSC infiltration. 49 Specifically, the activation of the NLRP3 inflammasome, NF-κB and IL-1β elevates chemokine secretion, including CXCLs or CCLs that recruit MDSCs into the premetastatic niches. 50 …”

“… 120 IL-1β expressing tumor cells express higher levels of G-CSF, multiple CXC chemokines, and vascular adhesion molecules that mediate G-MDSCs infiltration and enhance angiogenic and immunosuppressive properties. 49 Activation of MDSCs by IL-1β enhances their immunosuppressive activities through NF-κB signaling. Therefore, IL-1β inhibition may suppress MDSCs infiltration and function.…”