Summary
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.
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Acknowledgements
We thank all of the patients who contributed to this report and Yachiyo Kumamoto for her contribution to the immunofluorescent experiments.
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Dr. Isei reports personal fees from Ono Pharmaceutical CO., LTD., personal fees from Bristol-Myers Squibb, Novartis, Merck Co. and Inc., Toray Industries, Inc., Merck KGaA, Maruho Co., Ltd., and Kaken Pharmaceutical CO.,LTD., outside of the submitted work. Dr. Inoue reports grants from YAMAHA Motor, TAIHO Pharma, ONO Pharmaceutical and TAKEDA Pharmaceutical, outside of the submitted work. Dr. Imamura reports personal fees from Ono pharmaceutical co., LTD, MSD, and Bristol-Myers Squibb, outside the submitted work.
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Informed consent was obtained from the present patient in the study.
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Kunimasa, K., Isei, T., Nakamura, H. et al. Proliferative CD8(+) PD-1(+) T-cell infiltration in a pembrolizumab-induced cutaneous adverse reaction. Invest New Drugs 36, 1138–1142 (2018). https://doi.org/10.1007/s10637-018-0628-3
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DOI: https://doi.org/10.1007/s10637-018-0628-3