title: MAP Kinase Inhibition Promotes T Cell and Anti-tumor Activity in Combination with PD-L1 Checkpoint Blockade.
abstract: Targeted inhibition of mitogen-activated protein kinase (MAPK) kinase (MEK) can induce regression of tumors bearing activating mutations in the Ras pathway but rarely leads to tumor eradication. Although combining MEK inhibition with T-cell-directed immunotherapy might lead to more durable efficacy, T cell responses are themselves at least partially dependent on MEK activity. We show here that MEK inhibition did profoundly block naive CD8(+) T cell priming in tumor-bearing mice, but actually increased the number of effector-phenotype antigen-specific CD8(+) T cells within the tumor. MEK inhibition protected tumor-infiltrating CD8(+) T cells from death driven by chronic TCR stimulation while sparing cytotoxic activity. Combining MEK inhibition with anti-programmed death-ligand 1 (PD-L1) resulted in synergistic and durable tumor regression even where either agent alone was only modestly effective. Thus, despite the central importance of the MAP kinase pathway in some aspects of T cell function, MEK-targeted agents can be compatible with T-cell-dependent immunotherapy.
authors.affiliation: Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Peter J R
authors.initials: PJR
authors.lastname: Ebert
authors.affiliation: Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Jeanne
authors.initials: J
authors.lastname: Cheung
authors.affiliation: Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Yagai
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Erin
authors.initials: E
authors.lastname: McNamara
authors.affiliation: Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Hong
authors.affiliation: Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Marina
authors.initials: M
authors.lastname: Moskalenko
authors.affiliation: Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Gould
authors.affiliation: Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Heather
authors.initials: H
authors.lastname: Maecker
authors.affiliation: Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Bryan A
authors.initials: BA
authors.lastname: Irving
authors.affiliation: Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Jeong M
authors.initials: JM
authors.lastname: Kim
authors.affiliation: Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Marcia
authors.initials: M
authors.lastname: Belvin
authors.affiliation: Genentech, 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: mellman.ira@gene.com.
authors.forename: Ira
authors.initials: I
authors.lastname: Mellman
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D017209:Apoptosis; D001384:Azetidines / Q000008:administration & dosage / Q000494:pharmacology; D060890:B7-H1 Antigen / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D002277:Carcinoma / Q000276:immunology / Q000628:therapy*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000276:immunology / Q000628:therapy*; D004357:Drug Synergism; D004358:Drug Therapy; D004359:Drug Therapy, Combination; D048049:Extracellular Signal-Regulated MAP Kinases; D006801:Humans; D007167:Immunotherapy; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D058990:Molecular Targeted Therapy; D009368:Neoplasm Transplantation; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology
chemical_list: D000911:Antibodies, Monoclonal; D001384:Azetidines; D060890:B7-H1 Antigen; D010880:Piperidines; D048049:Extracellular Signal-Regulated MAP Kinases; C574276:cobimetinib