Genetic evolution of uveal melanoma guides the development of an inflammatory microenvironment

Abstract

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.

Single-cell analysis reveals new evolutionary complexity in uveal melanoma

“…These findings reveal a complex ecosystem of tumor and immune cells and suggest that they co-evolve along trajectories associated with specific sets of genomic aberrations 10,19 . It is interesting to speculate that the long latency and low metastatic rate of class 1 UMs may be due, at least in part, to immune surveillance, which could result from neoantigens generated by EIF1AX and SF3B1 mutations 20 .…”

Genetic and epigenetic insights into uveal melanoma

“…In UM, the connection between M2 macrophages and chromosomal alterations is still under investigation. However, a recent paper from Gezgin et al pointed out that early changes with gain of chromosome 8q are associated with macrophages infiltration while lack of BAP1 protein expression in monosomy and disomy 3 tumors is related to a higher T cell infiltration . Over decades, these clinical and histologic prognostic markers have been the gold standard to determine the risk for UM outcome and metastases.…”

“…However, a recent paper from Gezgin et al pointed out that early changes with gain of chromosome 8q are associated with macrophages infiltration while lack of BAP1 protein expression in monosomy and disomy 3 tumors is related to a higher T cell infiltration. 22 Over decades, these clinical and histologic prognostic markers have been the gold standard to determine the risk for UM outcome and metastases. Recent achievements in the genetic field have shed more light on the underlying genetic and epigenetic changes which are nowadays used for a more precise prognosis and may also allow for new diagnostic and therapeutic approaches in particular for metastatic disease.…”

Chemokine Receptor Expression Pattern Correlates to Progression of Conjunctival Melanocytic Lesions

“…We were not able to confirm this assumption with the results of our study, may be because of the influence of high (co-)expression of CXCR4, which is also suggested to play a role in tumorigenesis via lymphocyte infiltration. 14,15 Overexpression of CCR10 is associated with a worse prognosis, as described in cutaneous melanoma. 17 Adverse behavior of melanocytic lesions with CCR10 overexpression was also found in our study.…”

“…[9][10][11][12] Furthermore, chemokines play a role in inflammatory responses, 13,14 which might be involved in tumor progression. 14,15 Chemokine receptors are cytokine receptor-like G-linked proteins on the cell surface and are classified into four different groups, depending on the position of the cysteine residues. 10,11,14 It is suspected that tumor cells that express specific chemokine receptors tend to migrate toward the specific organ that produces the complementary ligand.…”