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

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

Author information

1
Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
2
Genentech, 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: mellman.ira@gene.com.

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.

PMID:
26944201
DOI:
10.1016/j.immuni.2016.01.024
[Indexed for MEDLINE]
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