title: Molecular profiling reveals a tumor-promoting phenotype of monocytes and macrophages in human cancer progression.
abstract: Monocytes and macrophages are major components of the tumor microenvironment, but their contributions to human cancer are poorly understood. We used molecular profiling combined with functional assays to investigate the role of these cells in human renal cell carcinoma (RCC). Blood monocytes from RCC patients displayed a tumor-promoting transcriptional profile that supported functions like angiogenesis and invasion. Induction of this protumor phenotype required an interleukin-1 receptor (IL-1R)-dependent mechanism. Indeed, targeting of IL-1-IL-1R axis in a human RCC xenograft model abrogated the protumor phenotype of tumor-associated macrophages (TAMs) and reduced tumor growth in vivo. Supporting this, meta-analysis of gene expression from human RCC tumors showed IL1B expression to correlate with myelomonocytic markers, protumor genes, and tumor staging. Analyzing RCC patient tumors confirmed the protumor phenotype of TAMs. These data provide direct evidence for a tumor-promoting role of monocytes and macrophages in human cancer and indicate IL-1-IL-1R as a possible therapeutic target.
authors.affiliation: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A(∗)STAR), Biopolis, Singapore 138648, Singapore.
authors.forename: Manesh
authors.initials: M
authors.lastname: Chittezhath
authors.affiliation: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A(∗)STAR), Biopolis, Singapore 138648, Singapore.
authors.forename: Manprit Kaur
authors.initials: MK
authors.lastname: Dhillon
authors.affiliation: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A(∗)STAR), Biopolis, Singapore 138648, Singapore.
authors.forename: Jyue Yuan
authors.initials: JY
authors.lastname: Lim
authors.affiliation: Laboratory of Myeloid Cell Immunology, VIB, Brussels 1050, Belgium; Cellular and Molecular Immunology Lab, Vrije Universiteit Brussel, Brussels 1050, Belgium.
authors.forename: Damya
authors.initials: D
authors.lastname: Laoui
authors.affiliation: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A(∗)STAR), Biopolis, Singapore 138648, Singapore.
authors.forename: Irina N
authors.initials: IN
authors.lastname: Shalova
authors.affiliation: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A(∗)STAR), Biopolis, Singapore 138648, Singapore.
authors.forename: Yi Ling
authors.initials: YL
authors.lastname: Teo
authors.affiliation: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A(∗)STAR), Biopolis, Singapore 138648, Singapore.
authors.forename: Jinmiao
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Urology, National University Health System, Lower Kent Ridge Road, Singapore 119074, Singapore.
authors.forename: Revathy
authors.initials: R
authors.lastname: Kamaraj
authors.affiliation: Department of Urology, National University Health System, Lower Kent Ridge Road, Singapore 119074, Singapore.
authors.forename: Lata
authors.initials: L
authors.lastname: Raman
authors.affiliation: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A(∗)STAR), Biopolis, Singapore 138648, Singapore.
authors.forename: Josephine
authors.initials: J
authors.lastname: Lum
authors.affiliation: Department of Pathology, National University Health System, Lower Kent Ridge Road, Singapore 119074, Singapore.
authors.forename: Thomas Paulraj
authors.initials: TP
authors.lastname: Thamboo
authors.affiliation: Department of Urology, National University Health System, Lower Kent Ridge Road, Singapore 119074, Singapore.
authors.forename: Edmund
authors.initials: E
authors.lastname: Chiong
authors.affiliation: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A(∗)STAR), Biopolis, Singapore 138648, Singapore.
authors.forename: Francesca
authors.initials: F
authors.lastname: Zolezzi
authors.affiliation: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A(∗)STAR), Biopolis, Singapore 138648, Singapore.
authors.forename: Henry
authors.initials: H
authors.lastname: Yang
authors.affiliation: Laboratory of Myeloid Cell Immunology, VIB, Brussels 1050, Belgium; Cellular and Molecular Immunology Lab, Vrije Universiteit Brussel, Brussels 1050, Belgium.
authors.forename: Jo A
authors.initials: JA
authors.lastname: Van Ginderachter
authors.affiliation: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A(∗)STAR), Biopolis, Singapore 138648, Singapore.
authors.forename: Michael
authors.initials: M
authors.lastname: Poidinger
authors.affiliation: Department of Haematology-Oncology, National University Health System, Lower Kent Ridge Road, Singapore 119074, Singapore.
authors.forename: Alvin S C
authors.initials: AS
authors.lastname: Wong
authors.affiliation: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A(∗)STAR), Biopolis, Singapore 138648, Singapore. Electronic address: subhra_biswas@immunol.a-star.edu.sg.
authors.forename: Subhra K
authors.initials: SK
authors.lastname: Biswas
mesh_terms: D000818:Animals; D002292:Carcinoma, Renal Cell / Q000276:immunology*; D049109:Cell Proliferation / Q000235:genetics; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D020869:Gene Expression Profiling; D006801:Humans; D007249:Inflammation / Q000276:immunology; D053590:Interleukin 1 Receptor Antagonist Protein / Q000494:pharmacology; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D016513:Mice, SCID; D009000:Monocytes / Q000276:immunology*; D053594:Myeloid Differentiation Factor 88; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D051996:Transcription Factor RelA / Q000235:genetics; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: D016207:Cytokines; C508585:IL1B protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; C498143:RELA protein, human; D017472:Receptors, Interleukin-1; D051996:Transcription Factor RelA