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Neutrophils recruit regulatory T‐cells into tumors via secretion of CCL17—A new mechanism of impaired antitumor immunity
Author(s) -
Mishalian Inbal,
Bayuh Rachel,
Eruslanov Evgeniy,
Michaeli Janna,
Levy Liran,
Zolotarov Lida,
Singhal Sunil,
Albelda Steven M.,
Granot Zvi,
Fridlender Zvi G.
Publication year - 2014
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.28770
Subject(s) - biology , immune system , secretion , ccl17 , immunology , flow cytometry , monoclonal antibody , cancer research , immunity , chemokine , cellular immunity , cytotoxic t cell , antibody , in vitro , endocrinology , cxcl10 , biochemistry
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.