Abstract
Purpose :
The immune microenvironment is thought to be a significant prognostic factor in uveal melanoma (UM) as the inflammatory phenotype is associated with the worst prognosis in UM, unlike other malignancies. Specifically, in UM cases characterized by monosomy 3, tumor-associated macrophages (TAMs) exhibit a predominant M2 polarization, known for their pro-angiogenic properties that actively contribute to tumor progression. Recent findings indicate a heightened gene expression of pigmentation in the presence of M2 macrophages, contrasting with M1 macrophages. The oncogenic potential of TAMs in conjunction with pigmentation remains unexplored in UM, particularly within the Asian population. Our study aimed to detect the prognostic relevance of TAMs and pigmentation markers such as TYRP1, TYRP2, SILV, and MITF expression levels in UM patients and their association with monosomy 3 and other clinicopathological parameters.
Methods :
Forty UM tissue samples underwent FISH to identify monosomy 3. Morphological changes in melanosomes in UM cases were analyzed by TEM. Immunohistochemistry was employed to assess M1 & M2 macrophages as well as pigmentation markers (TYRP1, TYRP2, SILV, and MITF) on UM tissue sections. mRNA expression of all pigmentation markers was quantified using qRT-PCR. ELISA was performed to quantify the expression of IL-10 and IL-12, downstream targets of M2 & M1 macrophages, respectively, in UM serum samples. The Cox proportional hazard model and log-rank test were used to determine the prognostic outcome of these markers.
Results :
The density of M2 macrophages was significantly increased in UM with monosomy 3 and high TYRP1, TYRP2, SILV, and MITF expression. UM cases demonstrated a significantly higher concentration of IL-10 compared to IL-12. Expression of M2 macrophages, monosomy 3, and expression of all pigmentation markers were correlated with high pigmentation. High expression of MITF protein along with M2/M1 macrophages and monosomy 3 showed reduced metastasis-free survival.
Conclusions :
The observed correlation suggests that high pigmentation could potentially influence the tumor microenvironment in UM, contributing to increased M2 macrophage densities and subsequent tumor progression. This might have a role in the absence of effective antitumor immune responses in UM patients. Our study could provide the development of new therapeutic options that can overcome the immunosuppressive effects in UM.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.