Polarization of tumor-associated neutrophil phenotype by TGF-beta: "N1" versus "N2" TAN.
TGF-beta blockade significantly slows tumor growth through many mechanisms, including activation of CD8(+) T cells and macrophages. Here, we show that TGF-beta 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-beta 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-beta within the tumor microenvironment induces a population of TAN with a protumor phenotype. TGF-beta blockade results in the recruitment and activation of TANs with an antitumor phenotype.
Fridlender
Zvi G
ZG
Thoracic Oncology Research Laboratory, 1016B ARC, University of Pennsylvania, Philadelphia, PA 19104-6160, USA. fridlender@hadassah.org.il
Sun
Jing
J
Kim
Samuel
S
Kapoor
Veena
V
Cheng
Guanjun
G
Ling
Leona
L
Worthen
G Scott
GS
Albelda
Steven M
SM
D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism; D053961:Azabicyclo Compounds / Q000494:pharmacology; D039481:CD11b Antigen / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D016764:Cell Polarity / Q000235:genetics / Q000276:immunology*; D002472:Cell Transformation, Viral; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008654:Mesothelioma / Q000235:genetics / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009504:Neutrophils / Q000276:immunology* / Q000473:pathology; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000276:immunology*; D023041:Xenograft Model Antitumor Assays / Q000379:methods
D000950:Antigens, Ly; D053961:Azabicyclo Compounds; D039481:CD11b Antigen; D016207:Cytokines; C480309:Ly6G antigen, mouse; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; C528106:SM16 compound; D016212:Transforming Growth Factor beta