title: A CCR4 antagonist reverses the tumor-promoting microenvironment of renal cancer.
abstract: Elevated expression of the chemokine receptor CCR4 in tumors is associated with poor prognosis in several cancers. Here, we have determined that CCR4 was highly expressed in human renal cell carcinoma (RCC) biopsies and observed abnormal levels of CCR4 ligands in RCC patient plasma. An antagonistic anti-CCR4 antibody had antitumor activity in the RENCA mouse model of RCC. CCR4 inhibition did not reduce the proportion of infiltrating leukocytes in the tumor microenvironment but altered the phenotype of myeloid cells, increased NK cell and Th1 cytokine levels, and reduced immature myeloid cell infiltrate and blood chemokine levels. In spite of prominent changes in the myeloid compartment, the anti-CCR4 antibody did not affect RENCA tumors in T cell-deficient mice, and treatment with an anti-class II MHC antibody abrogated its antitumor activity. We concluded that the effects of the anti-CCR4 antibody required the adaptive immune system and CD4+ T cells. Moreover, CCL17-induced IFN-γ production was reduced when Th1-polarized normal CD4+ T cells were exposed to the CCR4 ligand, evidencing the involvement of CCR4 in Th1/Th2 regulation. The anti-CCR4 antibody, alone or in combination with other immune modulators, is a potential treatment approach to human solid cancers with high levels of CCR4-expressing tumor-infiltrating leukocytes and abnormal plasma CCR4 ligand levels.
authors.forename: Chiara
authors.initials: C
authors.lastname: Berlato
authors.forename: Moddasar N
authors.initials: MN
authors.lastname: Khan
authors.forename: Tiziana
authors.initials: T
authors.lastname: Schioppa
authors.forename: Richard
authors.initials: R
authors.lastname: Thompson
authors.forename: Eleni
authors.initials: E
authors.lastname: Maniati
authors.forename: Anne
authors.initials: A
authors.lastname: Montfort
authors.forename: Maryam
authors.initials: M
authors.lastname: Jangani
authors.forename: Monica
authors.initials: M
authors.lastname: Canosa
authors.forename: Hagen
authors.initials: H
authors.lastname: Kulbe
authors.forename: Urs B
authors.initials: UB
authors.lastname: Hagemann
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Duncan
authors.forename: Laura
authors.initials: L
authors.lastname: Fletcher
authors.forename: Robert W
authors.initials: RW
authors.lastname: Wilkinson
authors.forename: Thomas
authors.initials: T
authors.lastname: Powles
authors.forename: Sergio A
authors.initials: SA
authors.lastname: Quezada
authors.forename: Frances R
authors.initials: FR
authors.lastname: Balkwill
mesh_terms: D000818:Animals; D000912:Antibodies, Neoplasm / Q000276:immunology / Q000494:pharmacology*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000235:genetics / Q000276:immunology*; D054414:Chemokine CCL17 / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D007680:Kidney Neoplasms; D007694:Killer Cells, Natural / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000235:genetics / Q000276:immunology*; D054398:Receptors, CCR4 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology*; D059016:Tumor Microenvironment / Q000187:drug effects / Q000235:genetics / Q000276:immunology*
chemical_list: D000912:Antibodies, Neoplasm; C106230:CCL17 protein, human; C515354:CCR4 protein, human; C499538:Ccl17 protein, mouse; C515355:Ccr4 protein, mouse; D054414:Chemokine CCL17; C573415:IFNG protein, human; C000611649:IFNG protein, mouse; D009363:Neoplasm Proteins; D054398:Receptors, CCR4; D007371:Interferon-gamma