Impact of MAPK Pathway Activation in BRAF(V600) Melanoma on T Cell and Dendritic Cell Function

Abstract

Constitutive upregulation of the MAPK pathway by a BRAF(V600) mutation occurs in about half of melanomas. This leads to increased oncogenic properties such as tumor cell invasion, metastatic potential, and resistance to apoptosis. Blockade of the MAPK pathway with highly specific kinase inhibitors induces unprecedented tumor response rates in patients with advanced BRAF(V600) mutant melanoma. Immune checkpoint blockade with monoclonal antibodies targeting cytotoxic T-lymphocyte antigen 4 and programed death-1/PD-L1 has also demonstrated striking anti-tumor activity in patients with advanced melanoma. Tumor responses are likely limited by multiple additional layers of immune suppression in the tumor microenvironment. There is emerging preclinical and clinical evidence suggesting that MAPK inhibition has a beneficial effect on the immunosuppressive tumor microenvironment, providing a strong rationale for combined immunotherapy and MAPK pathway inhibition in melanoma. The T cell response has been the main focus in the studies reported to date. Since dendritic cells (DCs) are important in the induction of tumor-specific T cell responses, the impact of MAPK pathway activation in melanoma on DC function is critical for the melanoma directed immune response. BRAF(V600E) melanoma cells modulate DCs through the MAPK pathway because its blockade in melanoma cells can reverse suppression of DC function. As both MEK/BRAF inhibition and immune checkpoint blockade have recently taken center stage in the treatment of melanoma, a deeper understanding of how MAPK pathway inhibition affects the tumor immune response is needed.

Keywords: BRAF; MEK; T cell; dendritic cell; immunotherapy; kinase inhibitor; melanoma.

Figure 1

Mechanisms that may lead to increased DC function upon MAPK pathway blockade in the tumor microenvironment. (A) Apoptosis/necrosis of melanoma cells results in release of tumor antigens that will presumably be available to DCs for cross presentation; (B) Increased expression of MDA through direct effect of MAPK pathway inhibition, potentially making them available to DCs for cross presentation, (C) decreased direct inhibition of DCs leading to increased IL-12 and TNF-α production.