Immunity
Volume 44, Issue 3, 15 March 2016, Pages 609-621
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Article
MAP Kinase Inhibition Promotes T Cell and Anti-tumor Activity in Combination with PD-L1 Checkpoint Blockade

https://doi.org/10.1016/j.immuni.2016.01.024Get rights and content
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Highlights

  • Pharmacologic inhibition of MEK potentiates rather than hinders anti-tumor T cells

  • MEK inhibitors nonetheless suppress anti-tumor priming in lymph nodes in vivo

  • MEK inhibitors potentiate anti-tumor T cells by impairing TCR-driven apoptosis

  • MEK inhibition combines with anti-PD-L1 treatment to yield durable tumor regression

Summary

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.

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2

Present address: Gilead, Foster City, CA 94404, USA

3

Present address: Cytomics Therapeutics, South San Francisco, CA 94080, USA