Polarization of Tumor-Associated Neutrophil Phenotype by TGF-β: "N1" versus "N2" TAN

Abstract

TGF-β blockade significantly slows tumor growth through many mechanisms, including activation of CD8+ T cells and macrophages. Here, we show that TGF-β blockade also increases neutrophil-attracting chemokines, resulting in an influx of CD11b+/Ly6G+ tumor-associated neutrophils (TANs) that are hypersegmented, more cytotoxic to tumor cells, and express higher levels of proinflammatory cytokines. Accordingly, following TGF-β blockade, depletion of these neutrophils significantly blunts antitumor effects of treatment and reduces CD8+ T cell activation. In contrast, in control tumors, neutrophil depletion decreases tumor growth and results in more activated CD8+ T cells intratumorally. Together, these data suggest that TGF-β within the tumor microenvironment induces a population of TAN with a protumor phenotype. TGF-β blockade results in the recruitment and activation of TANs with an antitumor phenotype. © 2009 Elsevier Inc. All rights reserved.