SCIENCE@home

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

C. Tannenbaum,P. Rayman,P. Pavicic,J. Kim,Wei Wei,Alexandra Polefko,W. Wallace,B. Rini,G. Morris-Stiff,D. Allende,T. Hamilton,J. Finke,C. Diaz-Montero

Published 2019 in Cancer immunology research

ABSTRACT

Induction of MDSCs and their recruitment to the tumor microenvironment is the result of a coordinated response by tumor stromal components to IL1β and its downstream mediators. These data provide a deeper understanding of MDSC development and function. 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 IL1β can drive the generation, accumulation, and functional capacity of MDSCs, the specific IL1β-induced inflammatory mediators contributing to these activities remain incompletely defined. Here, we identified IL1β-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, IL1β-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 IL1β-inducible molecules could mobilize PMN-MDSCs, but because they lacked the ability to upregulate IL1β-inducible CXCR2-directed chemokines or vascular adhesion molecules, additional PMN-MDSCs could not infiltrate tumors. IL1β-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 IL1β 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 IL1β expression in human renal cell carcinoma tumors. These studies demonstrated that IL1β 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.

PUBLICATION RECORD

CITATION MAP

EXTRACTION MAP

CLAIMS

  • No claims are published for this paper.

CONCEPTS

  • No concepts are published for this paper.

REFERENCES

Showing 1-55 of 55 references · Page 1 of 1

CITED BY

Showing 1-45 of 45 citing papers · Page 1 of 1