In many malignancies, a key immunoevasive event is when tumor cells inactivate genes encoding components of the antigen presentation machinery. With a defect in antigen presentation, tumor cells cannot present neoantigens on MHC class I on the cell surface and can thus evade recognition and eradication by cytotoxic T cells. Surprisingly, in contrast to most other malignancies, lack of MHC class I expression is associated with longer survival in patients with uveal melanoma. The reason for this discrepancy is not completely understood, but a tentative reason could be that the malignant clone is predominantly controlled by NK cells rather than T cells. Accordingly, maintained expression of MHC class I on malignant cells does not result in eradication by T cells (as the neoantigens are scarce), but rather allow ligation of inhibitory receptors on NK cells and evasion of NK cell cytotoxicity. Further support for a role for NK cells in uveal melanoma immunosurveillance comes from the finding that half of primary tumors displayed MICA staining, while none of the metastatic tumors did, indicating that downregulation of activating ligands may be a prerequisite for NK cell evasion to allow metastasis formation.
Participating lab members: PhD student Yassir Abdul Rahim, MSc Jonathan Björkquist