title: Paradoxical activation of T cells via augmented ERK signaling mediated by a RAF inhibitor.
abstract: RAF inhibitors selectively block ERK signaling in BRAF-mutant melanomas and have defined a genotype-guided approach to care for this disease. RAF inhibitors have the opposite effect in BRAF wild-type tumor cells, where they cause hyperactivation of ERK signaling. Here, we predict that RAF inhibitors can enhance T cell activation, based upon the observation that these agents paradoxically activate ERK signaling in BRAF wild-type cells. To test this hypothesis, we have evaluated the effects of the RAF inhibitor BMS908662 on T cell activation and signaling in vitro and in vivo. We observe that T cell activation is enhanced in a concentration-dependent manner and that this effect corresponds with increased ERK signaling, consistent with paradoxical activation of the pathway. Furthermore, we find that the combination of BMS908662 with CTLA-4 blockade in vivo potentiates T cell expansion, corresponding with hyperactivation of ERK signaling in T cells detectable ex vivo. Lastly, this combination demonstrates superior anti-tumor activity, compared to either agent alone, in two transplantable tumor models. This study provides clear evidence that RAF inhibitors can modulate T cell function by potentiating T cell activation in vitro and in vivo. Paradoxical activation of ERK signaling in T cells offers one mechanism to explain the enhanced antitumor activity seen when RAF inhibitors are combined with CTLA-4 blockade in preclinical models.
authors.affiliation: Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065.|Weill-Cornell Medical College, New York, NY 10065.
authors.forename: Margaret K
authors.initials: MK
authors.lastname: Callahan
authors.affiliation: Bristol-Myers Squibb Company, Princeton, NJ 08543.
authors.forename: Gregg
authors.initials: G
authors.lastname: Masters
authors.affiliation: Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY 10065.|Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065.|Weill-Cornell Medical College, New York, NY 10065.
authors.forename: Christine A
authors.initials: CA
authors.lastname: Pratilas
authors.affiliation: Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY 10065.|Weill-Cornell Medical College, New York, NY 10065.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Ariyan
authors.affiliation: Bristol-Myers Squibb Company, Princeton, NJ 08543.
authors.forename: Jessica
authors.initials: J
authors.lastname: Katz
authors.affiliation: Ludwig Center for Cancer Immunotherapy at Memorial Sloan-Kettering Cancer Center, New York, NY 10065.
authors.forename: Shigehisa
authors.initials: S
authors.lastname: Kitano
authors.affiliation: Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065.
authors.forename: Valerie
authors.initials: V
authors.lastname: Russell
authors.affiliation: Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065.
authors.forename: Ruth Ann
authors.initials: RA
authors.lastname: Gordon
authors.affiliation: Ludwig Center for Cancer Immunotherapy at Memorial Sloan-Kettering Cancer Center, New York, NY 10065.
authors.forename: Shachi
authors.initials: S
authors.lastname: Vyas
authors.affiliation: Ludwig Center for Cancer Immunotherapy at Memorial Sloan-Kettering Cancer Center, New York, NY 10065.
authors.forename: Jianda
authors.initials: J
authors.lastname: Yuan
authors.affiliation: Bristol-Myers Squibb Company, Princeton, NJ 08543.
authors.forename: Ashok
authors.initials: A
authors.lastname: Gupta
authors.affiliation: Bristol-Myers Squibb Company, Princeton, NJ 08543.
authors.forename: Jon M
authors.initials: JM
authors.lastname: Wigginton
authors.affiliation: Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065.|Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065.|Weill-Cornell Medical College, New York, NY 10065.
authors.forename: Neal
authors.initials: N
authors.lastname: Rosen
authors.affiliation: Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065.
authors.forename: Taha
authors.initials: T
authors.lastname: Merghoub
authors.affiliation: Bristol-Myers Squibb Company, Princeton, NJ 08543.
authors.forename: Maria
authors.initials: M
authors.lastname: Jure-Kunkel
authors.affiliation: Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065.|Ludwig Institute for Cancer Research, New York Branch, New York, NY 10065.|Ludwig Center for Cancer Immunotherapy at Memorial Sloan-Kettering Cancer Center, New York, NY 10065.|Weill-Cornell Medical College, New York, NY 10065.
authors.forename: Jedd D
authors.initials: JD
authors.lastname: Wolchok
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors; D002219:Carbamates / Q000008:administration & dosage / Q000494:pharmacology*; D002460:Cell Line; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays; D048490:raf Kinases / Q000037:antagonists & inhibitors*
chemical_list: C000593770:BMS 908662; D001562:Benzimidazoles; D060908:CTLA-4 Antigen; D002219:Carbamates; D018984:Epitopes, T-Lymphocyte; D047428:Protein Kinase Inhibitors; D048490:raf Kinases; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: BRAF; CTLA-4; Melanoma; RAF inhibitors; T cell; immunotherapy