Molecular profiling of primary uveal melanomas with tumor-infiltrating lymphocytes

Abstract

In contrast to other cancers, the presence of tumor-infiltrating lymphocytes (TILs) in uveal melanoma is associated with a poor prognosis. However, how TILs may promote disease progression and what regulates their infiltration has not yet been established. To address these clinically relevant outstanding questions, T cell, immune regulatory, and chemokine gene expression profiles of 57 enucleated uveal melanoma tumors were compared, encompassing 27 with TILs and 30 without,. Tumors with infiltrating lymphocytes expressed more CD8A mRNA, as well as IFNG, TGFB1, and FOXP3 transcripts. Other T helper associated cytokines and T helper transcription factors were not differentially expressed, nor were mediators of lymphocyte cytotoxicity. The immune inhibitors INDO, PDCA1, CTLA4, and LAG3, and the non-classical MHC Class I target of CD8+ T regulatory cells, HLA‑E, were significantly higher in tumors with TILs. FAS was also significantly higher. The C-C chemokine ligands CCL4, CCL5, and CCL20 were higher in tumors with TILs. Levels of CCL5 were most strongly correlated with levels of CD8A. Chemokine receptors were not differentially expressed. Molecular profiling of uveal melanoma tumors with TILs supports the existence of an immunosuppressive tumor microenvironment and suggests roles for CD8+ regulatory T cells, as well as specific chemokines, in fostering uveal melanoma disease progression.