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

Peter J R Ebert1, Jeanne Cheung1, Yagai Yang1

  • 1Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.

Immunity
|March 6, 2016
PubMed

Insights

MEK inhibition hinders naive T cell priming but boosts effector CD8(+) T cells within tumors. Combining MEK inhibitors with PD-L1 immunotherapy achieves synergistic, durable tumor regression.

Area of Science:

  • Immunology
  • Oncology
  • Molecular Biology

Background:

  • Mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitors induce tumor regression in Ras-mutated cancers but rarely lead to eradication.
  • T-cell-mediated immunotherapy offers durable efficacy, but T cell responses depend on MEK activity.

Purpose of the Study:

  • To investigate the impact of MEK inhibition on T cell function in cancer.
  • To evaluate the combination of MEK inhibition with anti-PD-L1 immunotherapy for enhanced anti-tumor efficacy.

Main Methods:

  • Utilized tumor-bearing mouse models.
  • Administered MEK inhibitors and anti-PD-L1 antibodies.
  • Assessed CD8(+) T cell priming, phenotype, and cytotoxic activity within tumors.

Main Results:

  • MEK inhibition blocked naive CD8(+) T cell priming but increased effector CD8(+) T cells in tumors.
  • MEK inhibition protected tumor-infiltrating CD8(+) T cells from chronic stimulation-induced death while preserving cytotoxic function.
  • Combination therapy synergistically eradicated tumors, outperforming monotherapies.

Conclusions:

  • MEK inhibition is compatible with T-cell-dependent immunotherapy despite MEK's role in T cell function.
  • Combining MEK inhibitors with PD-L1 blockade offers a promising strategy for durable cancer regression.

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