Inhibition of BRAF(V600E) Relieves IL-1– mediated T Cell Suppression by
Melanoma Tumor-associated Fibroblasts
Jahan S. Khalili, Shujuan Liu, Tania G. Rodríguez-Cruz, Mayra Whittington, Seth Wardell, Chengwen
Liu, Jieqing Chen, Minying Zhang, Yufeng Li, Richard W. Joseph, Suhendan Ekmekcioglu, Elizabeth
Grimm, Laszlo G. Radvanyi, Michael A. Davies, Patrick Hwu and Gregory Lizée
The BRAF oncogene demonstrates a characteristic mutation (V600E) in a significant fraction of
cutaneous melanomas, leading to constitutive activation of the MAP kinase pathway. This genetic
lesion endows tumor cells with proliferative and survival advantages, and metastatic melanoma patients
treated with the BRAF(V600E)-specific inhibitor vemurafenib have shown dramatic clinical responses.
Here, we show that BRAF(V600E) induces transcription of the IL-1α and IL-1β genes in both
melanocytes and melanoma cell lines and that this upregulation is specifically abrogated by targeted
BRAF(V600E) inhibitors. Furthermore, treatment of melanoma tumor-associated fibroblasts (TAFs) with
IL-1α/β significantly enhanced the ability of TAFs to suppress the proliferation and function of
melanoma antigen-specific cytotoxic T cells. IL-1α/β treatment of TAFs upregulated multiple
immunosuppressive factors, including COX-2 and the PD-1 ligands PD-L1 and PD-L2. Specific
BRAF(V600E) inhibitors largely abrogated the ability of melanoma cells to confer T cell-suppressive
properties on TAFs. These results support a model in which BRAF(V600E) promotes immune
suppression in the melanoma tumor environment through an IL-1-mediated mechanism involving
resident stromal fibroblasts. Based on these findings, combination therapies involving targeted BRAF
inhibition and T cell based immunotherapies are warranted.
.
