The BRAF–MAPK signaling pathway is essential for cancer-immune evasion in human melanoma cells

By H. Sumimoto, Fumie Imabayashi, T. Iwata, Y. Kawakami. Journal of Experimental Medicine, 2006

672 citations recorded by the source corpus.

The mitogen-activated protein kinase (MAPK) pathway is frequently activated in human cancers, leading to malignant phenotypes such as autonomous cellular proliferation. Here, we demonstrate a novel role of the activated MAPK pathway in immune evasion by melanoma cells with the mutation of BRAF, which encodes a MAPKKs, (BRAFV600E). MEK inhibitor U0126 or RNA interference (RNAi) for BRAFV600E decreased production of the immunosuppressive soluble factors interleukin (IL)-10, VEGF, or IL-6 from melanoma cells to levels comparable to those after signal transducer and activator of transcription (STAT)3 inactivation. The suppressive activity of the culture supernatants from the melanoma cells on the production of inflammatory cytokines IL-12 and tumor necrosis factor α by dendritic cells upon lipopolysaccharide stimulation was markedly reduced after transduction with BRAFV600E RNAi, comparable to the effects observed with STAT3 RNAi transduction. No additive or synergistic effects were observed by the simultaneous transduction of RNAi for both BRAFV600E and STAT3. Furthermore, specific DNA binding and transcriptional activity of STAT3 were not affected by down-regulation of the MAPK signaling with the BRAF RNAi. These results indicate that the MAPK signal, along with the STAT3 signal, is essential for immune evasion by human melanomas that have constitutively active MAPK signaling and is a potential molecular target for overcoming melanoma cell evasion of the immune system.

Subfields: Immunology, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/3f58729a5006cc8b0e498a6907bc9f4a48131781

How researchers see this paper

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In Immunology

1. A. Mantovani
2. A. Sica
3. P. Allavena
4. Guido Kroemer
5. L. Galluzzi
6. F. Balkwill
7. L. Zitvogel
8. M. Smyth

In Molecular Biology

1. Guido Kroemer
2. L. Galluzzi
3. A. Sica
4. L. Zitvogel
5. P. Allavena
6. A. Mantovani
7. F. Balkwill
8. M. Smyth

In Oncology

1. A. Mantovani
2. A. Sica
3. P. Allavena
4. F. Balkwill
5. Guido Kroemer
6. L. Galluzzi
7. L. Zitvogel
8. M. Smyth

Citations in the corpus

• Selective BRAF Inhibitors Induce Marked T-cell Infiltration into Human Metastatic Melanoma (2011, background): “In vitro experiments on mutant BRAF melanoma cell lines suggested that this may reflect inhibition of the release of immunosuppressive cytokines such as interleukin (IL)-10, VEGF, and IL-6 (11), or reflect increased melanoma cell antigen presentation, resulting in increased T-cell recognition of the”
• Adoptive immunotherapy for cancer: harnessing the T cell response (2012, neutral): “Onkojen çekilmesi ayrıca tümör hücrelerinin immünosüpresif sitokin üretmesini de azaltabilir (161).”
• Regulation of PD-L1: a novel role of pro-survival signalling in cancer. (2016, background): “The initial evidence that oncogenic activation of the MAPK pathway was associated with cancer cell immune evasion came from the finding that treatment with the mutant BRAF inhibitors was associated with a rapid increase in T-cell infiltration into the melanoma microenvironment [51, 52].”
• Combining Immunotherapy and Targeted Therapies in Cancer Treatment (2012, background): “A further link between oncogenic pathways and immunoregulation involves mutant BRAF, which drives the secretion of suppressive cytokines such as IL-10 and VEGFA from melanoma cell”
• STATs in cancer inflammation and immunity: a leading role for STAT3 (2009, neutral): “Importantly, the persistent activation of STAT3 intrinsic to tumour cells is transmitted to stromal inflammatory cells in the tumour microenvironmen”
• Mechanism of action of conventional and targeted anticancer therapies: reinstating immunosurveillance. (2013, background): “Gemcitabine, a nucleosideanalog, specifically reduces splenic MDSCs (Gr-1+/CD11b+ cells) in tumor-bearing mice, while leaving the effector functions of local NK cells unaffected (Suzuki et al., 2005).”
• Cancer-related inflammation (2008, background): “Members of the RAS family are the most frequently mutated dominant oncogenes in human cancer, and activated oncogenic components of the RAS–RAF signalling pathway, in turn, induce the production of tumour-promoting inflammatory chemokines and cytokine”