Selective BRAFV600E inhibition enhances T-cell recognition of melanoma without affecting lymphocyte function.

By Andrea Boni, Alexandria P. Cogdill, P. Dang, Durga Udayakumar, C. Njauw, C. Sloss, Cristina R. Ferrone, K. Flaherty, D. Lawrence, D. Fisher and 2 more. Cancer Research, 2010

727 citations recorded by the source corpus.

Targeted therapy against the BRAF/mitogen-activated protein kinase (MAPK) pathway is a promising new therapeutic approach for the treatment of melanoma. Treatment with selective BRAF inhibitors results in a high initial response rate but limited duration of response. To counter this, investigators propose combining this therapy with other targeted agents, addressing the issue of redundancy and signaling through different oncogenic pathways. An alternative approach is combining BRAF/MAPK-targeted agents with immunotherapy. Preliminary evidence suggests that oncogenic BRAF (BRAF(V600E)) contributes to immune escape and that blocking its activity via MAPK pathway inhibition leads to increased expression of melanocyte differentiation antigens (MDA). Recognition of MDAs is a critical component of the immunologic response to melanoma, and several forms of immunotherapy capitalize on this recognition. Among the various approaches to inhibiting BRAF/MAPK, broad MAPK pathway inhibition may have deleterious effects on T lymphocyte function. Here, we corroborate the role of oncogenic BRAF in immune evasion by melanoma cells through suppression of MDAs. We show that inhibition of the MAPK pathway with MAPK/extracellular signal-regulated kinase kinase (MEK) inhibitors or a specific inhibitor of BRAF(V600E) in melanoma cell lines and tumor digests results in increased levels of MDAs, which is associated with improved recognition by antigen-specific T lymphocytes. However, treatment with MEK inhibitors impairs T lymphocyte function, whereas T-cell function is preserved after treatment with a specific inhibitor of BRAF(V600E). These findings suggest that immune evasion of melanomas mediated by oncogenic BRAF may be reversed by targeted BRAF inhibition without compromising T-cell function. These findings have important implications for combined kinase-targeted therapy plus immunotherapy for melanoma.

Subfields: Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/9794928172b59b0477535e00d2ba2ff59dae0b38

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Citations in the corpus

The MAPK pathway across different malignancies: A new perspective (2014, background): “This could increase T-cell recognition of the tumor, leading to a successful immunotherapeutic approach.(53) The next proteins downstream, MEK1 and MEK2, have now been successfully targeted.”
Adoptive immunotherapy for cancer: harnessing the T cell response (2012, unknown): “Güz Sayısı 2012 | Cilt:5 | Sayı:6 İmmünoloji Çalışma Grubu 2012 uygulanması melanomada tümörle birleşmiş antijenlerin upregülasyonuna öncülük edip bu sayede T hücrelerinin tümörü tanımasını sağladığı gösterilmiştir (162).”
Selective BRAF Inhibitors Induce Marked T-cell Infiltration into Human Metastatic Melanoma (2011, background): “These findings corroborate the results of in vitro studies conducted on cell lines that suggest BRAF inhibitors do not compromise immune cell function and may increase immune cell recognition of melanoma cells (12, 13).”
Cytokines in Cancer Immunotherapy (2011, background): “In melanoma, BRAF mutations appear to enable immune evasion by suppressing the expression of melanoma differentiation antigens that typically serve as the targets for anti-tumor T cells [43].”
Combining Immunotherapy and Targeted Therapies in Cancer Treatment (2012, background): “In this context, an unexpected link between BRAF inhibitors and the expression of melanoma T cell antigens was recently uncovere”
Immune-based mechanisms of cytotoxic chemotherapy: implications for the design of novel and rationale-based combined treatments against cancer (2013, background): “Vemurafenib, a specific BRAF inhibitor recently approved for treatment of some melanomas, enhances the expression of several tumor antigens, enabling immune recognition by T lymphocytes.(138) Trastuzumab and cetuximab, monoclonal antibodies directed against tumor-associated receptor TK HER-2 and EGF”
Immune parameters affecting the efficacy of chemotherapeutic regimens (2011, background): “Moreover, a BRAF inhibitor increases expression of melanocyte differentiation antigens on melanoma cells whose epitopes can be recognized by specific T cells”
Oncogenic BRAF regulates oxidative metabolism via PGC1α and MITF (2013, unknown): “The relationship between BRAF and MITF is poorly understood because oncogenic BRAF and the ERK pathway promote MITF activation but also lead to its degradation (Hemesath et al., 1998; Wu et al., 2000; Wellbrock and Marais, 2005; Wellbrock et al., 2008; Boni et al., 2010).”