Roles For Braf Kinase Activating Mutations In Melanoma: Microenvironmental Immunosuppression

<p>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, I 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.<strong> </strong></p> <p><strong><br /></strong></p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2011

Author dc:creator

• Khalili, Jahan

Contributors dc:contributor

• Gregory Lizée, Ph.D.
• Patrick Hwu, M.D.
• Michael Davies, M.D., Ph.D.

• Melanoma
• Medicine and Health Sciences

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/213

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-1243