Inflammatory cell infiltrates in metastatic uveal melanoma


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Yamini Krishna1,Conni McCarthy2,Helen Kalirai2,Sarah Coupland3
1Royal Liverpool University Hospital,2University of Liverpool,3Royal Liverpool University Hospital and University of Liverpool

Abstract

Background

Uveal melanoma is an aggressive intraocular malignancy with up to 50% of patients developing metastatic disease, usually involving the liver, even several years after the primary treatment.  Current treatments for metastatic uveal melanoma (mUM) are limited and rarely prolong patient survival.  Immunotherapy trials for mUM are few, and to-date have demonstrated only marginal success.  High densities of tumour-associated-macrophages (TAMs) and infiltrating T-lymphocytes (TILs) in primary uveal melanoma are associated with poor prognosis.  However, little is known about the immune microenvironment of mUM.   Our aim was to examine the presence and distribution of TAMs and TILs in mUM within the liver.

Method

Whole tissue-sections of formal-fixed paraffin embedded liver mUM specimens (n=35) were examined by immunohistochemistry.  For TAMs, monoclonal-antibodies against CD68 and CD163 were used.  Macrophage density and morphology were scored using previous established systems.  Density and spatial distribution of TILs were highlighted using antibodies against CD3 (pan-lymphocyte marker), CD4 (T-helper cells) and CD8 (T-cytotoxic cells).

Results

CD68+ and CD163+ TAMs were seen within the tumour in all 35 specimens; their density was ‘moderate’ in 50% of cases, ‘few’ in 43% and the majority showed an ‘indeterminate’ phenotype.  CD3+ TILs were noted both within mUMs and surrounding the tumour.  Of these CD8+ TILs were ‘few’ in number within mUM but were predominantly seen peri-tumourally at the tumour/normal liver interface, whilst CD4+ TILs showed a high perivascular density within mUM.

Conclusion

CD68+ and CD163+ TAMs of ‘indeterminate’ morphology were observed in mUM, suggesting a tendency towards the pro-tumourigenic M2-phenotype.  CD4+ TILs were seen infiltrating mUM, whereas CD8+ TILs tended to be peri-tumoural.  The biological role of inflammatory cells in mUM requires further investigation, to determine if they represent potential targets for future immunotherapies in mUM.