title: Neutrophils recruit regulatory T-cells into tumors via secretion of CCL17--a new mechanism of impaired antitumor immunity.
abstract: The mechanisms by which tumor-associated neutrophils (TANs) affect tumor growth are to a large extent unknown. Regulatory T-cells (T-regs) are functionally immune-suppressive subsets of T-cells. Depletion or inhibition of T-regs can enhance antitumor immunity. We demonstrated both by RT-PCR and by ELISA that murine TANs secrete significant amounts of the T-regs chemoattractant, CCL17, much more than circulating or splenic neutrophils, and at a level progressively increasing during tumor development. Migration assays, both in vitro and in vivo, showed recruitment of T-regs by TANs, which was inhibited with anti-CCL17 monoclonal antibodies. Systemic neutrophil depletion in tumor-bearing mice using anti-Ly6G monoclonal antibodies reduced the migration of T-regs into the tumors. We further showed, using flow cytometry, that CCL17 secretion by TANs is not limited to mouse models of cancer but is also relevant to human TANs. Our results suggest a new indirect mechanism by which TANs may inhibit antitumor immune activity, thus promoting tumor growth. We further describe, for the first time, a clear link between TANs and T-regs acting together to impair antitumor immunity.
authors: Institute of Pulmonary Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors: Inbal
authors: I
authors: Mishalian
authors: Rachel
authors: R
authors: Bayuh
authors: Evgeniy
authors: E
authors: Eruslanov
authors: Janna
authors: J
authors: Michaeli
authors: Liran
authors: L
authors: Levy
authors: Lida
authors: L
authors: Zolotarov
authors: Sunil
authors: S
authors: Singhal
authors: Steven M
authors: SM
authors: Albelda
authors: Zvi
authors: Z
authors: Granot
authors: Zvi G
authors: ZG
authors: Fridlender
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D000950:Antigens, Ly / Q000276:immunology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000276:immunology; D054414:Chemokine CCL17 / Q000276:immunology*; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D008212:Lymphocyte Depletion; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D000950:Antigens, Ly; C499538:Ccl17 protein, mouse; D054414:Chemokine CCL17; C480309:Ly6G antigen, mouse
keywords: CCL17; immune avoidance; regulatory T-cells; tumor immunology; tumor-associated neutrophils