BRAF and MEK inhibitors differentially affect nivolumab-induced T cell activation by modulating the TCR and AKT signaling pathways
Related Experiment Video
Updated: Feb 1, 2026
Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries
Published on: January 22, 2019
Peng Yue1, Taylor Harper1, Silvia M Bacot1
1Office of Biotechnology Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, USA.
Abstract:
Immune checkpoint inhibitors (ICIs) such as the anti-PD-1 antibody Nivolumab, achieve remarkable clinical efficacy in patients with late stage cancers. However, only a small subset of patients benefit from this therapy. Numerous clinical trials are underway testing whether combining ICIs with other anti-cancer therapies can increase this response rate. For example, anti-PD-1/PD-L1 therapy combined with MAP kinase inhibition using BRAF inhibitors (BRAFi) and/or MEK inhibitors (MEKi) are in development for treatment of late stage melanomas. However, the benefits and underlying mechanisms of these combinatorial therapies remain unclear. In the current study, we assess the effects of MAPK inhibition on Nivolumab-induced T cell responses. Using an in vitro mixed lymphocyte reaction assay, we demonstrate that Nivolumab-induced T cell activation is highly heterogeneous. While BRAFi inhibits Nivolumab-induced cytokine production, T cell proliferation, activation markers (CD69, CD25), and Granzyme B in a substantial proportion of donor pairs, a small subset of donor pairs shows an additive effect. MEKi alone significantly inhibits Nivolumab-induced T cell activation; the addition of BRAFi significantly enhances this inhibitory effect. Mechanistically, the effects of BRAFi and/or MEKi on Nivolumab-induced T cell activation may be due to alteration of the activation of the AKT and T cell receptor (TCR) signaling pathways. Our results suggest that MAPK inhibition may not provide a clinical benefit for most melanoma patients being treated with anti-PD-1 therapy.
Insights
Combining BRAF inhibitors (BRAFi) or MEK inhibitors (MEKi) with anti-PD-1 therapy like Nivolumab may not benefit most melanoma patients. MAPK inhibition often hinders Nivolumab
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- Immune checkpoint inhibitors (ICIs), such as Nivolumab (anti-PD-1), show efficacy in late-stage cancers but benefit a limited patient subset.
- Combinatorial therapies, including ICIs with MAP kinase (MAPK) pathway inhibitors (BRAF inhibitors [BRAFi] and MEK inhibitors [MEKi]), are being investigated for melanoma to improve response rates.
Purpose of the Study:
- To investigate the effects of MAPK inhibition (BRAFi and MEKi) on Nivolumab-induced T cell responses.
- To elucidate the mechanisms underlying the efficacy and limitations of combining anti-PD-1 therapy with MAPK inhibitors.
Main Methods:
- Utilized an in vitro mixed lymphocyte reaction assay to assess T cell activation.
- Evaluated T cell cytokine production, proliferation, activation markers (CD69, CD25), and Granzyme B levels.
- Investigated the impact of BRAFi and MEKi, alone and in combination, on Nivolumab-treated T cells.
Main Results:
- Nivolumab-induced T cell activation was heterogeneous across donor pairs.
- BRAFi inhibited T cell responses in a significant proportion of donors, while a subset showed additive effects.
- MEKi alone inhibited T cell activation; combining MEKi with BRAFi further enhanced this inhibition.
- Observed potential alterations in AKT and T cell receptor (TCR) signaling pathways.
Conclusions:
- MAPK inhibition, particularly with MEKi and BRAFi, may counteract the T cell-activating effects of Nivolumab in many patients.
- The combination of anti-PD-1 therapy with MAPK inhibitors might not offer clinical benefits for the majority of melanoma patients.
- Further research is needed to understand the complex interplay between MAPK signaling and anti-PD-1 immunotherapy.
More Related Videos
09:32Light-mediated Reversible Modulation of the Mitogen-activated Protein Kinase Pathway during Cell Differentiation and Xenopus Embryonic Development
Published on: June 15, 2017
07:15Mechanism of Kemeng Fang's Inhibition of Podocyte Apoptosis in Rats with Membranous Nephropathy through the PI3K/AKT Signaling Pathway
Published on: August 23, 2024
Related Concept Videos
01:22PI3K/mTOR/AKT Signaling Pathway
01:24B Cell Activation and Differentiation
When naive B cells encounter a specific antigen that can bind to the B cell receptor (BCR) on their surface, they undergo sensitization to respond to the antigen's presence. Sensitization begins with...
03:14Notch Signaling Pathway
The Notch gene came into the limelight in 1914 after the discovery that its mutation in Drosophila melanogaster leads to a serrated (or "notched") wing margin phenotype. It was not...
02:33Hedgehog Signaling Pathway
01:19Interactions Between Signaling Pathways
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
01:21Cell-surface Signaling