MAP Kinase Inhibition Promotes T Cell and Anti-tumor Activity in Combination with PD-L1 Checkpoint Blockade

Immunity. 2016 Mar 15;44(3):609-621. doi: 10.1016/j.immuni.2016.01.024. Epub 2016 Mar 2.


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.

MeSH terms

  • Animals
  • Antibodies, Monoclonal / administration & dosage
  • Apoptosis
  • Azetidines / administration & dosage
  • Azetidines / pharmacology
  • B7-H1 Antigen / immunology*
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / immunology*
  • Carcinoma / immunology
  • Carcinoma / therapy*
  • Cell Cycle Checkpoints / drug effects
  • Cell Line, Tumor
  • Colonic Neoplasms / immunology
  • Colonic Neoplasms / therapy*
  • Drug Synergism
  • Drug Therapy
  • Drug Therapy, Combination
  • Extracellular Signal-Regulated MAP Kinases
  • Humans
  • Immunotherapy*
  • Lymphocyte Activation / drug effects
  • Mice
  • Mice, Inbred BALB C
  • Molecular Targeted Therapy
  • Neoplasm Transplantation
  • Piperidines / administration & dosage
  • Piperidines / pharmacology


  • Antibodies, Monoclonal
  • Azetidines
  • B7-H1 Antigen
  • Piperidines
  • Extracellular Signal-Regulated MAP Kinases
  • cobimetinib