Intracellular accumulation of PD-1 molecules in circulating T lymphocytes in advanced malignant melanoma: an implication
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ORIGINAL ARTICLE
Intracellular accumulation of PD‑1 molecules in circulating T lymphocytes in advanced malignant melanoma: an implication for immune evasion mechanism Ryo Takahashi1 · Yohei Sato2 · Momoko Kimishima2 · Tetsuo Shiohara1,2 · Manabu Ohyama1,2 Received: 20 March 2020 / Accepted: 21 June 2020 © Japan Society of Clinical Oncology 2020
Abstract Background 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. Methods 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. Results Increase in (sur)PD-1 and intracellular PD-1 ((int)PD-1+) expression was characteristic for AMM T cells. After shortterm 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). Conclusions 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. Keywords PD-1 · Nivolumab · Advanced malignant melanoma · Cutaneous immunotherapy-specific immune-related adverse events · irAEs Abbreviations 7-AAD 7-Aminoactinomycin D AMM Advanced stage malignant melanoma BrA Brefeldin A Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10147-020-01732-8) contains supplementary material, which is available to authorized users. * Manabu Ohyama [email protected]‑u.ac.jp 1
Flow Cytometry Core Facility, Kyorin University Graduate School of Medicine, Tokyo, Japan
Department of Dermatology, Kyorin University Faculty of Medicine, 6‑20‑2 Shinkawa, Mitaka city, Tokyo 181‑8611, Japan
2
CMV Cytomegalovirus Ctl Control CTL Cytotoxic T lymphocyte HC Healthy controls irAEs Immune-related adverse events IFN Interferon (int)PD-1 Intracellular PD-1 mAb Monoclonal antibody MFI Mean fluorescence intensity (sur)PD-1 Cell su
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