Immunomodulatory Properties of BRAF and MEK Inhibitors Used for Melanoma Therapy—Paradoxical ERK Activation and Beyond

Jung, Thomas; Haist, Maximilian; Kuske, Michael; Grabbe, Stephan; Bros, Matthias

doi:10.3390/ijms22189890

Cited by 15 publications

(17 citation statements)

References 107 publications

(144 reference statements)

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“…These cells suppressed the activation and proliferation of melanoma-specific cytotoxic T cells, thus promoting an immunosuppressive TME ( 54 ). In murine models and human samples of BRAF -mutant melanoma, tumors induced the accumulation of regulatory T cells (Treg), which limited effector T cell activity ( 55 ). BRAF -mutated tumors did not only exhibit an enhanced infiltration by immunosuppressive immune cell populations but they also up-regulate the expression of genes associated with immunosuppression, such as CTLA-4, PD-L1, or HLA-G ( 55 ).…”

Section: Discussionmentioning

confidence: 99%

PD-L1+ neutrophils as novel biomarkers for stage IV melanoma patients treated with nivolumab

et al. 2022

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Melanoma displays a rising incidence, and the mortality associated with metastatic form remains high. Monoclonal antibodies that block programmed death (PD-1) and PD Ligand 1 (PD-L1) network have revolutionized the history of metastatic disease. PD-L1 is expressed on several immune cells and can be also expressed on human neutrophils (PMNs). The role of peripheral blood PMNs as predictive biomarkers in anti-PD-1 therapy of melanoma is largely unknown. In this study, we aimed to determine activation status and PD-L1 expression on human neutrophils as possible novel biomarkers in stage IV melanoma patients (MPs). We found that PMNs from MPs displayed an activated phenotype and increased PD-L1 levels compared to healthy controls (HCs). Patients with lower PD-L1+ PMN frequencies displayed better progression-free survival (PFS) and overall survival (OS) compared to patients with high PD-L1+ PMN frequencies. Multivariate analysis showed that PD-L1+ PMNs predicted patient outcome in BRAF wild type MP subgroup but not in BRAF mutated MPs. PD-L1+ PMN frequency emerges as a novel biomarker in stage IV BRAF wild type MPs undergoing anti-PD-1 immunotherapy. Our findings suggest further evaluation of the role of neutrophil subsets and their mediators in melanoma patients undergoing immunotherapy.

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Section: Discussionmentioning

confidence: 99%

PD-L1+ neutrophils as novel biomarkers for stage IV melanoma patients treated with nivolumab

et al. 2022

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“…Other groups have also tested the effect of BRAFi and MEKi on DCs (reviewed in [ 13 ]). Hajek et al showed that murine bone marrow-derived (BM)-DCs increased the expression of CD80 and CD86 after treatment with dabra, D + T, and V + C, and of MHC cl.…”

Section: Discussionmentioning

confidence: 99%

“…BRAF V600 can be targeted with specific kinase inhibitors (BRAFi), i.e., vemurafenib (vemu; the first inhibitor approved by the FDA in 2011 as single treatment [ 10 ]), dabrafenib (dabra), or encorafenib, which have become a standard therapy in patients with this mutation [ 7 , 10 , 11 , 12 ]. Although the BRAFi are designed to target the mutated form, they show some paradox effects on wild type BRAF, resulting in an amplification of the signal [ 13 ]. To preempt the common relapses caused by resistant tumor variants [ 14 ], the BRAF V600 inhibitors were then combined with MEK inhibitors (MEKi), i.e., cobimetinib (cobi), trametinib (tram) [ 7 ], or binimetinib, which has been shown to increase progression-free survival significantly [ 13 , 15 , 16 ].…”

Section: Introductionmentioning

confidence: 99%

“…Although the BRAFi are designed to target the mutated form, they show some paradox effects on wild type BRAF, resulting in an amplification of the signal [ 13 ]. To preempt the common relapses caused by resistant tumor variants [ 14 ], the BRAF V600 inhibitors were then combined with MEK inhibitors (MEKi), i.e., cobimetinib (cobi), trametinib (tram) [ 7 ], or binimetinib, which has been shown to increase progression-free survival significantly [ 13 , 15 , 16 ]. MEKi inhibit the non-mutated MEK, blocking the pathway in tumor and healthy cells alike.…”

Section: Introductionmentioning

confidence: 99%

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BRAF and MEK Inhibitors Affect Dendritic-Cell Maturation and T-Cell Stimulation

Hoyer

Eberlein

Berking

et al. 2021

IJMS

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BRAF and MEK inhibitor (BRAFi/MEKi) combinations are currently the standard treatment for patients with BRAFV600 mutant metastatic melanoma. Since the RAS/RAF/MEK/ERK-pathway is crucial for the function of different immune cells, we postulated an effect on their function and thus interference with anti-tumor immunity. Therefore, we examined the influence of BRAFi/MEKi, either as single agent or in combination, on the maturation of monocyte-derived dendritic cells (moDCs) and their interaction with T cells. DCs matured in the presence of vemurafenib or vemurafenib/cobimetinib altered their cytokine secretion and surface marker expression profile. Upon the antigen-specific stimulation of CD8+ and CD4+ T cells with these DCs or with T2.A1 cells in the presence of BRAFi/MEKi, we detected a lower expression of activation markers on and a lower cytokine secretion by these T cells. However, treatment with any of the inhibitors alone or in combination did not change the avidity of CD8+ T cells in peptide titration assays with T2.A1 cells. T-helper cell/DC interaction is a bi-directional process that normally results in DC activation. Vemurafenib and vemurafenib/cobimetinib completely abolished the helper T-cell-mediated upregulation of CD70, CD80, and CD86 but not CD25 on the DCs. The combination of dabrafenib/trametinib affected DC maturation and activation as well as T-cell activation less than combined vemurafenib/cobimetinib did. Hence, for a potential combination with immunotherapy, our data indicate the superiority of dabrafenib/trametinib treatment.

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“…The BRAF V600 mutations are a representative gene mutation in melanoma and are detected in approximately 50% of patients with malignant melanoma. This gene mutation causes activation of the MAPK downstream pathway [22]. The second most frequent mutation in malignant melanoma is NRAS, which is related to the regulation of PI3K and MAPK [23].…”

Section: Malignant Melanomamentioning

confidence: 99%

The Influences of Omega-3 Polyunsaturated Fatty Acids on the Development of Skin Cancers

Minokawa¹,

Sawada²,

Nakamura³

2021

Diagnostics

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Dietary nutrition intake is essential for human beings and influences various physiological and pathological actions in the human body. Among various nutritional factors, dietary intake of omega-3 polyunsaturated fatty acids (PUFAs) has been shown to have various beneficial effects against inflammatory diseases. In addition to their therapeutic potency against inflammation, omega-3 PUFAs have also been shown to have anti-tumor effects via various mechanisms, such as cell arrest and apoptosis. To date, limited information is available on these effects in cutaneous malignancies. In this review, we focused on the effect of omega-3 PUFAs on skin cancers, especially malignant melanoma, basal cell carcinoma, lymphoma, and squamous cell carcinoma and discussed the detailed molecular mechanism of the omega-3 PUFA-mediated anti-tumor response. We also explored the molecular mechanisms mediated by epigenetic modifications, cell adhesion molecules, and anti-tumor immune responses.

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Immunomodulatory Properties of BRAF and MEK Inhibitors Used for Melanoma Therapy—Paradoxical ERK Activation and Beyond

Cited by 15 publications

References 107 publications

PD-L1+ neutrophils as novel biomarkers for stage IV melanoma patients treated with nivolumab

PD-L1+ neutrophils as novel biomarkers for stage IV melanoma patients treated with nivolumab

BRAF and MEK Inhibitors Affect Dendritic-Cell Maturation and T-Cell Stimulation

The Influences of Omega-3 Polyunsaturated Fatty Acids on the Development of Skin Cancers

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