Proliferative CD8(+) PD-1(+) T-cell infiltration in a pembrolizumab-induced cutaneous adverse reaction

Pembrolizumab, a humanized monoclonal immunoglobulin (Ig) G4 antibody that is directed against the human cell surface receptor PD-1, is a PD-1 pathway inhibitor that has been approved to treat various malignant diseases, including advanced non-small cell lung cancer (NSCLC). PD-1 is the major inhibitory receptor regulating T-cell exhaustion, and T-cells with high PD-1 expression lose their ability to eliminate cancer. PD-1 pathway blockade by pembrolizumab reinvigorates exhausted T-cells and restores their antitumor immune responses. However, reinvigorated T-cells also evoke immune-related adverse effects (irAEs), which stem from the restored activity. Currently, the pathogenic mechanisms of irAEs have not been sufficiently determined. We experienced a patient with NSCLC with high PD-L1 expression and cervical lymph node metastases, who demonstrated a good clinical response to first line pembrolizumab but suffered from a severe cutaneous adverse event. Both of his skin lesions and cervical metastases showed extensive CD8(+) PD-1(+) T-cell infiltration in immunofluorescence analysis. This finding suggests a possible contribution of reinvigorated CD8(+) PD-1(+) T-cells in anti-PD-1 therapy-induced skin rash. Intriguingly, CD8(+) T-cells in the skin rash showed higher Ki-67 expression, a proliferation marker, than those in the cervical lymph node lesion. This is the first report of an association between proliferative CD8(+) PD-1(+) T-cells and irAEs.