title: The immune microenvironment confers resistance to MAPK pathway inhibitors through macrophage-derived TNFα.
abstract: Recently, the rationale for combining targeted therapy with immunotherapy has come to light, but our understanding of the immune response during MAPK pathway inhibitor treatment is limited. We discovered that the immune microenvironment can act as a source of resistance to MAPK pathway-targeted therapy, and moreover during treatment this source becomes reinforced. In particular, we identified macrophage-derived TNFα as a crucial melanoma growth factor that provides resistance to MAPK pathway inhibitors through the lineage transcription factor MITF (microphthalmia transcription factor). Most strikingly, in BRAF-mutant melanomas of patients and BRAF(V600E) melanoma allografts, MAPK pathway inhibitors increased the number of tumor-associated macrophages, and TNFα and MITF expression. Inhibiting TNFα signaling with IκB kinase inhibitors profoundly enhanced the efficacy of MAPK pathway inhibitors by targeting not only the melanoma cells but also the microenvironment. In summary, we identify the immune microenvironment as a novel source of resistance and reveal a new strategy to improve the efficacy of targeted therapy in melanoma.
  
  
  CONCLUSIONS
  This study identifies the immune microenvironment as a source of resistance to MAPK pathway inhibitors through macrophage-derived TNFα, and reveals that in patients on treatment this source becomes reinforced. Inhibiting IκB kinase enhances the efficacy of MAPK pathway inhibitors, which identifies this approach as a potential novel strategy to improve targeted therapy in melanoma.
authors.affiliation: Manchester Cancer Research Centre, Wellcome Trust Center for Cell Matrix Research, Faculty of Life Sciences, The University of Manchester, Michael Smith Building, Oxford Road, Manchester, M13 9PT, UK.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Smith
authors.affiliation: Division of Cancer Biology, The Institute of Cancer Research, Chester Beatty Laboratories, 237 Fulham Road, SW3 6JB, UK.|Molecular Oncology Group, Cancer Research UK Manchester Institute, The University of Manchester, Wilmslow Road, Manchester, M20 4BX, UK.
authors.forename: Berta
authors.initials: B
authors.lastname: Sanchez-Laorden
authors.affiliation: Division of Cancer Biology, The Institute of Cancer Research, Chester Beatty Laboratories, 237 Fulham Road, SW3 6JB, UK.
authors.forename: Kate
authors.initials: K
authors.lastname: O'Brien
authors.affiliation: Manchester Cancer Research Centre, Wellcome Trust Center for Cell Matrix Research, Faculty of Life Sciences, The University of Manchester, Michael Smith Building, Oxford Road, Manchester, M13 9PT, UK.
authors.forename: Holly
authors.initials: H
authors.lastname: Brunton
authors.affiliation: Manchester Cancer Research Centre, Wellcome Trust Center for Cell Matrix Research, Faculty of Life Sciences, The University of Manchester, Michael Smith Building, Oxford Road, Manchester, M13 9PT, UK.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Ferguson
authors.affiliation: Manchester Cancer Research Centre, Wellcome Trust Center for Cell Matrix Research, Faculty of Life Sciences, The University of Manchester, Michael Smith Building, Oxford Road, Manchester, M13 9PT, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Young
authors.affiliation: Division of Cancer Biology, The Institute of Cancer Research, Chester Beatty Laboratories, 237 Fulham Road, SW3 6JB, UK.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Dhomen
authors.affiliation: Department of Medicine, Massachusetts General Hospital, 55 Fruit St, Boston, MA, USA.
authors.forename: Keith T
authors.initials: KT
authors.lastname: Flaherty
authors.affiliation: Department of Medicine, Massachusetts General Hospital, 55 Fruit St, Boston, MA, USA.
authors.forename: Dennie T
authors.initials: DT
authors.lastname: Frederick
authors.affiliation: Divison of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Zachary A
authors.initials: ZA
authors.lastname: Cooper
authors.affiliation: Divison of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Wargo
authors.affiliation: Division of Cancer Biology, The Institute of Cancer Research, Chester Beatty Laboratories, 237 Fulham Road, SW3 6JB, UK.|Molecular Oncology Group, Cancer Research UK Manchester Institute, The University of Manchester, Wilmslow Road, Manchester, M20 4BX, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Marais
authors.affiliation: Manchester Cancer Research Centre, Wellcome Trust Center for Cell Matrix Research, Faculty of Life Sciences, The University of Manchester, Michael Smith Building, Oxford Road, Manchester, M13 9PT, UK.
authors.forename: Claudia
authors.initials: C
authors.lastname: Wellbrock
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D004195:Disease Models, Animal; D015870:Gene Expression; D006801:Humans; D020935:MAP Kinase Signaling System; D008544:Melanocytes / Q000276:immunology* / Q000378:metabolism*; D008545:Melanoma / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D051739:Microphthalmia-Associated Transcription Factor / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D059016:Tumor Microenvironment / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
chemical_list: D051739:Microphthalmia-Associated Transcription Factor; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D048493:Proto-Oncogene Proteins B-raf