The Clinical Significance of Programmed Death1 Ligand-1 Expression on Leukemia Cells in Adult T Cell Leukemia Patients.

[Purpose and background] Adult T-cell leukemia/lymphoma (ATLL) caused by HTLV-I virus infection is one of the most aggressive lymphoid malignancies with short prognosis, of which best-reported median survival by combined chemotherapy is 13 months. Even at the disease onset, opportunistic infections are frequently complicated. Thus, host immune system both against tumor and infection is considered to be severely impaired in ATLL patients. However precise mechanism underlying that immunodeficiency still remains undetermined. Recently the lines of evidence that co-inhibitory molecules;programmed death-1/programmed death-1 ligand (PD-1/PD-L1) pathway in T-cell activation seems to play a crucial role in tumor escape from host immune surveillance system have been accumulated. In this study, we investigated the expression of PD-L1 on ATLL cells (CD4⁺/CD25+), and as their counterparts, CD4⁺ lymphocytes from HTLV-I asymptomatic carriers (ACs) to define their clinical significance.

[Patients and Methods] Peripheral blood CD4⁺ lymphocytes from 11 ATLL patients (9; untreated, 2; progressive state), 12 ACs and 2 healthy donors (HDs) were investigated for PD-L1 expression. We simultaneously measured co-inhibitory receptor, PD-1, expression on CD8⁺ HTLV-I Tax-specific cytotoxic lymphocytes (anti-Tax CTLs), as a marker of immunity against HTLV-I.

[Results] PD-L1 expression was detected on CD4⁺ lymphocytes in 3 of the 11 ATLL patients and 2 of them were in progressive state. In contrast, none of the ACs or HDs expressed PD-L1 on CD4⁺ lymphocytes, while those cultured with IL-2 for 48hs transiently expressed PD-L1. Anti-Tax CTLs were detected in 6 of the 11 ATLL patients and all of those CTL expressed PD-1 simultaneously. Anti-Tax CTLs were not detected in the 2 cases in progressive state. Anti-Tax CTLs were detected in 9 of 12 ACs, and PD-1 also co-expressed on those CTLs.

[Conclusions] CD4⁺ ATLL cells in progressive state expressed cell surface PD-L1, but not in untreated patients or ACs. This is a striking finding that exclusively aggressive form of ATLL tumor cells expressed cell surface PD-L1, which renders tumor cells to evade from host immune surveillance systems. Nonetheless large scale studies are needed to confirm these findings. In addition, Interestingly, co-inhibitory molecule PD-1 expressed on anti-Tax CTLs in not only ATLL patients but also ACs. Because PD-1 expression of CTL means “exhausted”, our observation suggests that anti-HTLV-I virus immunity is already exhausted both ATLL patients and ACs. Further experiments are warranted to define the significance of the correlation between PD-L1 on ATLL cells and PD-1 on anti-HTLV-I CTL in ATLL patients and ACs.