BRAF Inhibition Is Associated with Enhanced Melanoma Antigen Expression and a More Favorable Tumor Microenvironment in Patients with Metastatic Melanoma

Abstract

Purpose: To evaluate the effects of BRAF inhibition on the tumor microenvironment in patients with metastatic melanoma.Experimental Design: Thirty-five biopsies were collected from 16 patients with metastatic melanoma pretreatment (day 0) and at 10 to 14 days after initiation of treatment with either BRAF inhibitor alone (vemurafenib) or BRAF þ MEK inhibition (dabrafenib þ trametinib) and were also taken at time of progression. Biopsies were analyzed for melanoma antigens, T-cell markers, and immunomodulatory cytokines.Results: Treatment with either BRAF inhibitor alone or BRAF þ MEK inhibitor was associated with an increased expression of melanoma antigens and an increase in CD8þ T-cell infiltrate. This was also associated with a decrease in immunosuppressive cytokines [interleukin (IL)-6 and IL-8] and an increase in markers of T-cell cytotoxicity. Interestingly, expression of exhaustion markers TIM-3 and PD1 and the immunosuppressive ligand PDL1 was increased on treatment. A decrease in melanoma antigen expression and CD8 T-cell infiltrate was noted at time of progression on BRAF inhibitor alone and was reversed with combined BRAF and MEK inhibition.Conclusions: Together, these data suggest that treatment with BRAF inhibition enhances melanoma antigen expression and facilitates T-cell cytotoxicity and a more favorable tumor microenvironment, providing support for potential synergy of BRAF-targeted therapy and immunotherapy. Interestingly, markers of T-cell exhaustion and the immunosuppressive ligand PDL1 are also increased with BRAF inhibition, further implying that immune checkpoint blockade may be critical in augmenting responses to BRAF-targeted therapy in patients with melanoma.

Targeted agents and immunotherapies: optimizing outcomes in melanoma

“…In preclinical models and in patients, expression of MITF is upregulated following BRAF inhibition, with associated large-magnitude, although variable, increases in the expression of lineage antigens, such as gp100, melan-A, and tyrosinase-related proteins 1 and 2 (REFS 106,107). Whether increased expression of these antigens alone offers the opportunity for pre-existing tumourinfiltrating CD8 + T cells to recognize and contribute to the eliminaton of melanoma cells remains unknown; however, the observation that tumour-infiltrating lymphocyte counts are increased early in the course of BRAF-inhibitor therapy, when compared with those of tumour biopsy samples taken from the same patients immediately before therapy, supports this concept 107,108 . The characteristics of these lymphocytes have been described only preliminarily 109 , therefore, their contributions to therapeutic responses are unclear -markers of T-cell activation have been documented, but so have markers of T-cell exhaustion 104 .…”

“…These observations raised concerns that MEK inhibitors might not be a useful targeted-therapy backbone for combination immunotherapy, and that BRAF-MEK combination therapy might not be as capable of potentiating an immune response as BRAF-inhibition alone. However, increasing evidence from preclinical in vivo experience with MEK inhibitors 110 , and analyses of serial tumour-biopsy specimens from patients receiving combined BRAF-MEK-inhibitor therapy suggest a positive effect on the expression of MITF and melanocyte lineage antigens, and that T-cell infiltration persists under such treatment 107 . Moreover, a compelling additional observation indicates that MEK inhibitors can disrupt a deleterious signalling circuit between tumour cells and the so-called 'M2-like' macrophage population, which impair effector T-cell entry into tumours and drive melanomacell growth 111 .…”

Management of Italian Patients With Advanced Non–Small-Cell Lung Cancer After Second-Line Treatment: Results of the Longitudinal Phase of the LIFE Observational Study

“…Accumulating evidence has shown that mitogen-activated protein kinase (MAPK) inhibitors are capable of restraining the tumor growth and profoundly enhancing antitumor immunity in the following aspects 115 : (1) upregulate the antigen expressed on the tumor cells 116 ; (2) increase the numbers of tumor infiltrating CD8 þ cells 116,117 ; and (3) protect CTL from death by chronic TCR stimulation. 118 Current data showed that v-Raf murine sarcoma viral oncogene homolog B (BRAF) inhibitor-resistant tumor cells harbored an activated MAPK pathway and high expression of PD-L1.…”

Immune Checkpoint Inhibitors in the Treatment of Melanoma: From Basic Science to Clinical Application

“…Molecularly targeted agents are also being combined with immune checkpoint inhibitors. BRAF inhibition, which is FDA-approved for the treatment of metastatic melanoma expressing the activating BRAF V600E mutation, has been shown to increase MHC expression, tumor antigen presentation, and T-cell infiltration (98)(99)(100)(101)(102). Similarly, MEK inhibitors have been shown to improve CD8+ T-cell activity in preclinical models in combination with PD-1 blockade (103).…”