Genetic evolution of uveal melanoma guides the development of an inflammatory microenvironment
Uveal melanoma (UM) is characterized by a number of genetic aberrations that follow a certain chronology and are tightly linked to tumor recurrence and survival. Loss of chromosome 3, bi-allelic loss of BAP1 expression, and gain in chromosome 8q have been associated with metastasis formation and death, while loss of chromosome 3 has been associated with the influx of macrophages and T cells. We used a set of genetically-classified UM to study immune infiltration in the context of their genetic evolution. We show in two independent cohorts that lack of BAP1 expression is associated with an increased density of CD3+ T cells and CD8+ T cells. The presence of extra copies of chromosome 8q in disomy 3 tumors with a normal BAP1 expression is associated with an increased influx of macrophages (but not T cells). Therefore, we propose that the genetic evolution of UM is associated with changes in the inflammatory phenotype. Early changes resulting in gain of chromosome 8q may activate macrophage infiltration, while sequential loss of BAP1 expression seems to drive T cell infiltration in UM.
|Keywords||BAP1, Chromosome, Infiltration, Lymphocytes, Macrophages, T cells|
|Sponsor||This project was supported by Algemene Nederlandse Vereniging Ter Voorkoming van Blindheid (ANVVB), Stichting Blinden Penning, Landelijke Stichting voor Blinden en Slechtzienden (LSBS), Novartis Foundation, Stichting Nederlands Oogheelkundig Onderzoek (SNOO), Rotterdamse Stichting Blindenbelangen, and the European Union Horizon 2020 program UM Cure (Project number: 667787).|
|Persistent URL||dx.doi.org/10.1007/s00262-017-1991-1, hdl.handle.net/1765/99134|
|Journal||Cancer Immunology, Immunotherapy: other biological response modifications|
Gezgin, G, Dogrusöz, M, van Essen, T.H, Kroes, W.G, Luyten, G, van der Velden, P.A, … Jager, M.J. (2017). Genetic evolution of uveal melanoma guides the development of an inflammatory microenvironment. Cancer Immunology, Immunotherapy: other biological response modifications, 66(7), 903–912. doi:10.1007/s00262-017-1991-1