Selective BRAFV600E Inhibition Enhances T-Cell Recognition of Melanoma without Affecting Lymphocyte Function

Abstract

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. Cancer Res; 70(13); 5213-9. ©2010 AACR.

Enhancer-targeted genome editing selectively blocks innate resistance to oncokinase inhibition

“…3). These results are consistent with other work implicating MITF in melanoma survival (Haq et al 2013) 754 Genome Research www.genome.org therefore regulates two contrary effects of BRAF inhibition, namely, induction of melanocyte differentiation, which is an anti-tumorigenic effect important for immune cell recognition of melanoma (Kono et al 2006;Boni et al 2010;Liu et al 2013), and the pro-tumorigenic effect of engaging innate drug resistance to BRAF inhibition.…”

B-Raf Regulation of Integrin α4β1-mediated Resistance to Shear Stress through Changes in Cell Spreading and Cytoskeletal Association in T Cells

“…Sorafenib is a multikinase inhibitor once higher concentrations have been reached, but it is most specific for C-Raf (6 nM IC 50 ) and B-Raf (22 nM IC 50 ) and is still used in the clinic for the treatment of advanced renal cell carcinoma or hepatocellular carcinoma (29). The findings presented in this work should cause a reevaluation of clinical use of sorafenib having potential off-target effects on T cells (72)(73)(74). The effects of sorafenib on ␣4␤1 integrin could impact T cell migration and homing to sites of inflammation or potentially effector functions (75)(76)(77).…”

Immune-based mechanisms of cytotoxic chemotherapy: implications for the design of novel and rationale-based combined treatments against cancer

“…137 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 EGFR, respectively, augment antigen presentation through the formation of immune complexes, leading to stimulation of T-cell-mediated immune responses. 139,140 Altogether, these observations pave the way to clinical studies aimed at evaluating the possible synergism of targeted compounds and immunotherapy strategies.…”