Intracellular accumulation of PD-1 molecules in circulating T lymphocytes in advanced malignant melanoma: an implication for immune evasion mechanism

The blockade of cell surface PD-1 (_(sur)PD-1) by monoclonal antibodies, represented by nivolumab, provides the strategy to treat advanced malignant melanoma (AMM). The intracellular presence of PD-1 molecules have been reported in some T cell subsets, however, their kinetic association with those expressed on the cell surface, let alone their significance in antitumor immunity has been ill-investigated.

Intracellular PD-1 expression status in T cell subsets in AMM cases during nivolumab administration was chronologically characterized. The kinetics of PD-1 molecules within AMM-derived T cells was assessed in vitro in conjunction with their functional properties.

Increase in _(sur)PD-1 and intracellular PD-1 (_(int)PD-1⁺) expression was characteristic for AMM T cells. After short-term culture, virtually _(sur)PD-1^- nivolumab-treated AMM T cells restore _(sur)PD-1 expression, which could not be explained by the detachment of nivolumab from PD-1 epitopes alone. The blockade of trans-Golgi network resulted in the decrease in the extent of _(sur)PD-1 recovery, suggesting the translocation of accumulated _(int)PD-1 to the cell surface. Antigen-specific PD-1⁺ T cells significantly increased in _(int)PD-1⁺ cells after treatment. In addition, a surge in _(int)PD-1⁺CD4⁺ T cells was observed prior to the emergence of skin rash as an immune-related adverse event (irAE).

Accumulated _(int)PD-1 in T cells may contribute to enhanced immune evasion in AMM. Evaluation of intracellular PD-1 expression would be useful for better management of nivolumab-treated AMM patients in view of predicting treatment response and the incidence of irAE. Our findings further support the necessity of periodical administration of nivolumab for treating AMM.