Becas SEOM and inflammatory toxicities. This information is of great importance to understand the mechanism of action of antibodies like ipilimumab, and be able to compare it with the effects of the upcoming immune checkpoint inhibiting antibodies blocking PD-1 and PD-L1. Finally, Lidia has been working in an original project that is entirely based on her own preliminary data on the effects of immune and inflammatory cytokines on response and resistance to BRAF targeted therapies. Her studies have unveiled a remarkable phenomenon of de-differentiation changes as a melanoma adaptive resistance to both inflammatory cytokines and BRAF inhibitors. Her studies challenge current dogma and have high implications for the near future development of combinations of targeted therapies and immunotherapy strategies. Such a combination of independently active therapies for patients with melanoma has been a longstanding interest in my laboratory, and we have developed suitable in vitro and in vivo model systems to correctly test combinatorial therapies for BRAF mutant melanoma. Lidia has taken full advantage of these opportunities and has single-handy opened a new line of research in my laboratory. There is controversy on the effects of BRAF inhibitors to increase the expression of melanoma tumor antigens, with some groups having provided clear evidence that this is the case but others reporting that melanosomal tumor antigens and immune recognition actually decrease upon BRAF inhibitor therapy. Lidia set up to analyze this important issue in a systematic and novel way. Her data supports a scenario where the discrepancies could be attributed to different timing of events in different cell lines, and she continues to fully explore this hypothesis. Furthermore, Lidia has incorporated novel concepts into her research that help further understand the complicated interaction between BRAF inhibitors and immunotherapy. It has been recently noted that melanoma cells can de-differentiate in the neural crest differentiation pathway in response to inflammatory cytokines released by tumor infiltrating lymphocytes. This leads to a decrease in melanosomal tumor antigen expression and may be detrimental for the testing of immunotherapy. In addition, Lidia’s preliminary data shows that this same immune cell-provided signal actually protects melanoma cells from the antitumor activity of BRAF inhibitors. We certainly need to better understand these phenomena that Lidia has uncovered and analyze them in a mechanistic way. To do so, Lidia is now collaborating with nanotechnology investigators from Caltech (California Institute of Technology, Pasadena, CA) applying novel single cell functional proteomics assays to better understand the effects of melanoma de-differentiation adaptive resistance responses. In addition to her impressive performance in her time in my laboratory, Lidia is an outstanding colleague and a very highly valued member of the laboratory. It is a pleasure to have her around and I thank the SEOM scholarship committee for having invested in Lidia to allow her to be in my laboratory. In summary, I hope I have conveyed that Dr. Lidia Robert has done an outstanding job under the funding from SEOM, and that this grant has been of great help to advance her career. Please contact me by email at aribas@ mednet.ucla.edu or by phone at 310-206-3928 if further information is required. Cordially,
Antoni Ribas, M.D., Ph.D. Professor of Medicine, Hematology-Oncology Professor of Surgery, Surgical Oncology Professor of Molecular and Medical Pharmacology Director, Tumor Immunology Program, Jonsson Comprehensive Cancer Center (JCCC) David Geffen School of Medicine, University of California Los Angeles (UCLA)
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