title: Type I cytokines synergize with oncogene inhibition to induce tumor growth arrest.
abstract: Both targeted inhibition of oncogenic driver mutations and immune-based therapies show efficacy in treatment of patients with metastatic cancer, but responses can be either short lived or incompletely effective. Oncogene inhibition can augment the efficacy of immune-based therapy, but mechanisms by which these two interventions might cooperate are incompletely resolved. Using a novel transplantable BRAF(V600E)-mutant murine melanoma model (SB-3123), we explored potential mechanisms of synergy between the selective BRAF(V600E) inhibitor vemurafenib and adoptive cell transfer (ACT)-based immunotherapy. We found that vemurafenib cooperated with ACT to delay melanoma progression without significantly affecting tumor infiltration or effector function of endogenous or adoptively transferred CD8(+) T cells, as previously observed. Instead, we found that the T-cell cytokines IFNγ and TNFα synergized with vemurafenib to induce cell-cycle arrest of tumor cells in vitro. This combinatorial effect was recapitulated in human melanoma-derived cell lines and was restricted to cancers bearing a BRAF(V600E) mutation. Molecular profiling of treated SB-3123 indicated that the provision of vemurafenib promoted the sensitization of SB-3123 to the antiproliferative effects of T-cell effector cytokines. The unexpected finding that immune cytokines synergize with oncogene inhibitors to induce growth arrest has major implications for understanding cancer biology at the intersection of oncogenic and immune signaling and provides a basis for design of combinatorial therapeutic approaches for patients with metastatic cancer.
authors.affiliation: Surgery Branch, Center for Cancer Research, National Cancer Institute (NCI), US National Institutes of Health (NIH), Bethesda, Maryland. restifo@nih.gov nacquavella@miami.edu cleverdc@mail.nih.gov.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Acquavella
authors.affiliation: Surgery Branch, Center for Cancer Research, National Cancer Institute (NCI), US National Institutes of Health (NIH), Bethesda, Maryland. restifo@nih.gov nacquavella@miami.edu cleverdc@mail.nih.gov.
authors.forename: David
authors.initials: D
authors.lastname: Clever
authors.affiliation: Surgery Branch, Center for Cancer Research, National Cancer Institute (NCI), US National Institutes of Health (NIH), Bethesda, Maryland.
authors.forename: Zhiya
authors.initials: Z
authors.lastname: Yu
authors.affiliation: Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland.
authors.forename: Melody
authors.initials: M
authors.lastname: Roelke-Parker
authors.affiliation: Surgery Branch, Center for Cancer Research, National Cancer Institute (NCI), US National Institutes of Health (NIH), Bethesda, Maryland.
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Palmer
authors.affiliation: Surgery Branch, Center for Cancer Research, National Cancer Institute (NCI), US National Institutes of Health (NIH), Bethesda, Maryland.
authors.forename: Liqiang
authors.initials: L
authors.lastname: Xi
authors.affiliation: Surgery Branch, Center for Cancer Research, National Cancer Institute (NCI), US National Institutes of Health (NIH), Bethesda, Maryland.
authors.forename: Holger
authors.initials: H
authors.lastname: Pflicke
authors.affiliation: Experimental Transplantation and Immunology Branch, Center for Cancer Research, National Cancer Institute (NCI), US National Institutes of Health (NIH), Bethesda, Maryland.
authors.forename: Yun
authors.initials: Y
authors.lastname: Ji
authors.affiliation: Surgery Branch, Center for Cancer Research, National Cancer Institute (NCI), US National Institutes of Health (NIH), Bethesda, Maryland.
authors.forename: Alena
authors.initials: A
authors.lastname: Gros
authors.affiliation: Surgery Branch, Center for Cancer Research, National Cancer Institute (NCI), US National Institutes of Health (NIH), Bethesda, Maryland.
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Hanada
authors.affiliation: Division of Preclinical Innovation, U.S. National Institutes of Health Chemical Genomics Center, National Center for Advancing Translational Sciences, Rockville, Maryland. Cancer Research United Kingdom Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, United Kingdom.
authors.forename: Ian S
authors.initials: IS
authors.lastname: Goldlust
authors.affiliation: Surgery Branch, Center for Cancer Research, National Cancer Institute (NCI), US National Institutes of Health (NIH), Bethesda, Maryland.
authors.forename: Gautam U
authors.initials: GU
authors.lastname: Mehta
authors.affiliation: Surgery Branch, Center for Cancer Research, National Cancer Institute (NCI), US National Institutes of Health (NIH), Bethesda, Maryland.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Klebanoff
authors.affiliation: Surgery Branch, Center for Cancer Research, National Cancer Institute (NCI), US National Institutes of Health (NIH), Bethesda, Maryland. Cancer Research United Kingdom Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, United Kingdom.
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Crompton
authors.affiliation: Surgery Branch, Center for Cancer Research, National Cancer Institute (NCI), US National Institutes of Health (NIH), Bethesda, Maryland.
authors.forename: Madhusudhanan
authors.initials: M
authors.lastname: Sukumar
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, Ohio. Department of Genetics & Genome Sciences Case Western Reserve University, Cleveland, Ohio.
authors.forename: James J
authors.initials: JJ
authors.lastname: Morrow
authors.affiliation: Surgery Branch, Center for Cancer Research, National Cancer Institute (NCI), US National Institutes of Health (NIH), Bethesda, Maryland.
authors.forename: Zulmarie
authors.initials: Z
authors.lastname: Franco
authors.affiliation: Experimental Transplantation and Immunology Branch, Center for Cancer Research, National Cancer Institute (NCI), US National Institutes of Health (NIH), Bethesda, Maryland.
authors.forename: Luca
authors.initials: L
authors.lastname: Gattinoni
authors.affiliation: Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland.
authors.forename: Hui
authors.initials: H
authors.lastname: Liu
authors.affiliation: Sidra Medical and Research Center, Doha, Qatar.
authors.forename: Ena
authors.initials: E
authors.lastname: Wang
authors.affiliation: Sidra Medical and Research Center, Doha, Qatar.
authors.forename: Francesco
authors.initials: F
authors.lastname: Marincola
authors.affiliation: Department of Transfusion Medicine, Cell Processing Section, National Institutes of Health (NIH), Bethesda, Maryland.
authors.forename: David F
authors.initials: DF
authors.lastname: Stroncek
authors.affiliation: Surgery Branch, Center for Cancer Research, National Cancer Institute (NCI), US National Institutes of Health (NIH), Bethesda, Maryland.
authors.forename: Chyi-Chia R
authors.initials: CC
authors.lastname: Lee
authors.affiliation: Surgery Branch, Center for Cancer Research, National Cancer Institute (NCI), US National Institutes of Health (NIH), Bethesda, Maryland.
authors.forename: Mark
authors.initials: M
authors.lastname: Raffeld
authors.affiliation: Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Marcus W
authors.initials: MW
authors.lastname: Bosenberg
authors.affiliation: Surgery Branch, Center for Cancer Research, National Cancer Institute (NCI), US National Institutes of Health (NIH), Bethesda, Maryland.
authors.forename: Rahul
authors.initials: R
authors.lastname: Roychoudhuri
authors.affiliation: Surgery Branch, Center for Cancer Research, National Cancer Institute (NCI), US National Institutes of Health (NIH), Bethesda, Maryland. restifo@nih.gov nacquavella@miami.edu cleverdc@mail.nih.gov.
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Restifo
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D045744:Cell Line, Tumor; D016207:Cytokines / Q000276:immunology*; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D006801:Humans; D016219:Immunotherapy, Adoptive; D007211:Indoles / Q000627:therapeutic use*; D008545:Melanoma / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D009362:Neoplasm Metastasis / Q000628:therapy*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D015398:Signal Transduction; D013449:Sulfonamides / Q000627:therapeutic use*; D000077484:Vemurafenib
chemical_list: D016207:Cytokines; D007211:Indoles; D013449:Sulfonamides; D000077484:Vemurafenib; D048493:Proto-Oncogene Proteins B-raf