Estudo da expressão imuno-histoquímica do ligando de morte programada 1 (Pd-L1) em melanoma uveal

• Ano de defesa: 2018
• Autor(a) principal: Zoroquiain Velez, Jose Pablo [UNIFESP]
• Tipo de documento: Tese
• Tipo de acesso: Acesso aberto
• Idioma: spa
• Instituição de defesa: Universidade Federal de São Paulo (UNIFESP)
• Palavras-chave em Português: Neoplastic cells; Pd-L1 expression; Melanoma uveal; Alvos terapêuticos; Imuno-histoquímica; Ligando de morte programada
• Link de acesso: https://sucupira.capes.gov.br/sucupira/public/consultas/coleta/trabalhoConclusao/viewTrabalhoConclusao.jsf?popup=true&id_trabalho=6743521; https://repositorio.unifesp.br/handle/11600/52873

Purpose: Programmed cell death-1/ligand (PD-1/PD-L1) interaction negatively regulates T-cell activity. PD-L1 expression in tumor cells, antigen-presenting cells and lymphocytes of the tumor microenvironment is associated with response to treatment with PD1/PD-L1 inhibitors, but there is still debate on the cutoff value that correlates with responders. In uveal melanoma (UM), 40% of patients will develop liver metastases and 90% will succumb to their disease. The aim of this study is to analyze PD-L1 expression as a prognostic marker and as a possible therapeutic target for UM. Methods: Sixty-seven enucleated eyes from UM patients with relevant clinical information were analyzed. Immunostaining was performed with the anti-PDL1 E1L3N clone and with the retinal pigmented epithelium as an internal positive control. PD-L1 knockdown in the OCM-1 cell line was used as a negative control. Two methods of quantification of PD-L1 expression were used: the conventional method that describes >5% membranous staining in neoplastic cells as positive, and an alternative that defines positivity as >5% in either neoplastic or non-neoplastic cells (NNCs). Univariate and multivariate analysis were used to evaluate association of PD-L1 with survival. Results: PD-L1 expression was positive relative to neoplastic cells and NNCs counts in 46.3% and 55.2% of the cases, respectively. On univariate analysis, neoplastic cells and NNCs PD-L1 expression was associated with a longer metastasis free survival (MFS; P=0.04 and P=0.007). However, on multivariate analysis, only NNCs positivity was associated with longer MFS (P=0.01). Furthermore, neoplastic and NNCs PD-L1 expression was associated with decreased tumor infiltrating lymphocytes (TIL, P=0.02). Conclusions: The commercially available anti PD-L1 monoclonal antibody (E1L3N) shows high sensitivity and specificity in UM. PD-L1, when expressed in UMs, is associated with better patient outcome and decreased TIL. These results support the evaluation of anti-PD1/PD-L1 therapy in UM. To determine the best cutoff value, further studies from patients enrolled in clinical trials treated with PD1/PD-L1 inhibitors are necessary.