Immunological effects of BRAF+MEK inhibition

Abstract

Recent developments in immunotherapy have prolonged overall survival in metastatic melanoma with the possibility to reach a long-term benefit. Targeted therapies based on BRAF and MEK inhibition also seem to have a long-term beneficial effect, which is more evident in patients with favorable baseline characteristics, namely normal levels of lactate dehydrogenase, without brain metastases, and low tumor burden. This long-term benefit of targeted therapies might be related to an immune-modulation: indeed BRAF and MEK inhibitors affect tumor microenvironment and immune surveillance, and it has been shown that patients with complete response to targeted treatment have a pre-existing favorable immunologic signature.

Keywords: BRAF; MEK; advanced melanoma; immune therapy; target therapy.

Figure 1.

‘Easy’ and ‘difficult’ patients. The ‘easy’ patients present some characteristics (e.g., no brain metastasis, low tumor burden, normal LDH) that result in active immune surveillance against cancer cells. Such immune surveillance may be pre-existing and responsible for reaching complete response. On the other hand, immune surveillance is impaired in difficult patients, who commonly present brain metastasis, high tumor burden, and high LDH.

Figure 2.

Effects of BRAF-MEK inhibition on melanoma cells and tumor microenvironment. Therapy with BRAF and MEK inhibitors induces profound changes in antigen display, and expression of MHC, IFNAR, and CD73 on tumor cells. These changes are also evident on tumor microenvironment: namely they result in reduction of adenosine, diminished Treg and MDSC presence, and increased activity of CD4-CD8+ lymphocytes.