title: KIT oncogene inhibition drives intratumoral macrophage M2 polarization.
abstract: Tumor-associated macrophages (TAMs) are a major component of the cancer microenvironment. Modulation of TAMs is under intense investigation because they are thought to be nearly always of the M2 subtype, which supports tumor growth. Gastrointestinal stromal tumor (GIST) is the most common human sarcoma and typically results from an activating mutation in the KIT oncogene. Using a spontaneous mouse model of GIST and 57 freshly procured human GISTs, we discovered that TAMs displayed an M1-like phenotype and function at baseline. In both mice and humans, the KIT oncoprotein inhibitor imatinib polarized TAMs to become M2-like, a process which involved TAM interaction with apoptotic tumor cells leading to the induction of CCAAT/enhancer binding protein (C/EBP) transcription factors. In human GISTs that eventually developed resistance to imatinib, TAMs reverted to an M1-like phenotype and had a similar gene expression profile as TAMs from untreated human GISTs. Therefore, TAM polarization depends on tumor cell oncogene activity and has important implications for immunotherapeutic strategies in human cancers.
authors: Department of Surgery, 2 Department of Developmental Biology, and 3 Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065.
authors: Michael J
authors: MJ
authors: Cavnar
authors: Shan
authors: S
authors: Zeng
authors: Teresa S
authors: TS
authors: Kim
authors: Eric C
authors: EC
authors: Sorenson
authors: Lee M
authors: LM
authors: Ocuin
authors: Vinod P
authors: VP
authors: Balachandran
authors: Adrian M
authors: AM
authors: Seifert
authors: Jonathan B
authors: JB
authors: Greer
authors: Rachel
authors: R
authors: Popow
authors: Megan H
authors: MH
authors: Crawley
authors: Noah A
authors: NA
authors: Cohen
authors: Benjamin L
authors: BL
authors: Green
authors: Ferdinand
authors: F
authors: Rossi
authors: Peter
authors: P
authors: Besmer
authors: Cristina R
authors: CR
authors: Antonescu
authors: Ronald P
authors: RP
authors: DeMatteo
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D017209:Apoptosis; D001549:Benzamides / Q000737:chemistry; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D049109:Cell Proliferation; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D000068877:Imatinib Mesylate; D007249:Inflammation; D008264:Macrophages / Q000276:immunology*; D008297:Male; D051379:Mice; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D010879:Piperazines / Q000737:chemistry; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism*; D011743:Pyrimidines / Q000737:chemistry; D012509:Sarcoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*
chemical_list: D001549:Benzamides; D022762:CCAAT-Enhancer-Binding Proteins; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit