Local and Systemic Immune Response Against Tumor Specific and Tumor-associated Antigens in Patients with Localized Uveal Melanoma (UM)

Abstract Text: Mutations in the splicing factor SF3B1 generate immunogenic public neoantigens (neoAgs) allowing tracking tumor-Ag specific T cell response. SF3B1Mut related neoAg specific T-cells have been found in the blood of metastatic UM (mUM) patients.
Using tetramers specific for SF3B1mut related neoAgs or for a melanocyte differentiation (Melan-A) Ag, we evidenced the presence of memory CD8 T cells for these tumor Ags in the blood of patients bearing SF3B1mut UM tumors indicating that the immune system has been in contact with these tumor Ag.
As the eye is an immune privileged site without draining lymph nodes, where would happen the priming step is not obvious. To assess the immune response towards tumor-specific Ag in the primary eye tumor, we studied 20 enucleated patients whose tumor was SF3B1wt. In tumors, we observed a large proportion of CD8+ T cells expressing CD39 and PD-1 suggesting local neoAg reactivity. Among them, 1-10% were specific for Melan-A. Using single cell RNAseq, we are currently characterizing the expanded clonotypes and their associate transcriptome in three patients.
Notably, only 1 out of 8 patients with Melan-A infiltrates in the eye harbored memory Melan-A specific CD8 T cells in the blood while in the 7 other patients, the Melan-A were still naïve (CCR7+CD45RA+) suggesting an absence of systemic response or a failure to detect it in the blood.

Conclusion: An anti-tumor immune response takes place in the eye since the early stage of tumor development without clear systemic response in many cases.