Divergent local and systemic antitumor response in primary uveal melanomas
Uveal melanoma (UM) is the most common cancer of the eye. The loss of chromosome-3 (M3) is associated with high risk of metastases. M3-tumors are more infiltrated by T-lymphocytes than low-risk disomic-3 (D3) tumors, contrasting with other tumor types in which T-cell infiltration correlates with better prognosis. Whether these T-cells represent an anti-tumor response and how these T-cells would be primed in the eye are both unknown. Herein, we characterized the T-cells infiltrating primary UMs. CD8+ and Treg cells were more abundant in M3- than in D3-tumors. CD39+PD-1+CD8+ T-cells were enriched in M3-tumors suggesting specific responses to tumor-antigen (Ag) as confirmed using HLA-A2:Melan-A tetramers. ScRNAseq-VDJ analysis of T-cells evidenced high numbers of proliferating CD39+PD1+CD8+ clonal expansions suggesting in-situ anti-tumor Ag responses. TCRseq and tumor-Ag tetramer staining characterized the recirculation pattern of the anti-tumor responses in M3- and D3-tumors. Thus, tumor-Ag responses occur in localized UMs raising the question of the priming mechanisms in the absence of known lymphatic drainage. Overall design: we studied the phenotype of the T cells found in primary UM at the time of diagnosis using multicolor flow cytometry, single cell transcriptomic (scRNAseq) associated to single cell TCR repertoire analysis with multiplex tetramer staining and bulk TCR sequencing for alpha and beta chains. CITE_Seq Demultiplexing HLA-A2:Melan-A HTO Barcode_sequence COH4_84 HLA-A2:Melan-A AACCTTTGCCACTGC COH4_56 HLA-A2:Melan-A AACCTTTGCCACTGC COH4_76 HLA-A2:Melan-A AACCTTTGCCACTGC