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HLA class II is a good prognostic factor in ATLL
Table 4. Prognostic factors associated with overall survival in patients with adult T-cell leukemia/lymphoma. Univariate analysis
Characteristics
HLA class II+
HLA class II+/miPD-L1+ JCOG-PI (high) Age>70 years
Ann Arbor stage III, IV
Elevated LDH (>normal)
HR (95% CI)
0.386 (0.233-0.617)
0.276 (0.146-0.482) 1.841 (1.186-2.819) 1.709 (1.106-2.608) 1.801 (1.002-3.583)
0.982 (0.651-1.492)
P
<0.0001*
<0.0001*
0.0071*
0.0164
0.0491*
0.9344
Multivariate analysis HR (95% CI)
P
0.441 (0.263-0.714)
1.841 (1.163-2.883) 1.441 (0.925-2.217) 1.661 (0.915-3.325) 0.934 (0.605-1,447)
0.0007*
0.0096* 0.1048 0.0982 0.7582
ATLL: adult T-cell leukemia/lymphoma; HR: hazard ratio; 95% CI: 95% confidence interval; HLA: human leukocyte antigen; miPD-L1: microenvironmental programmed cell death ligand-1; JCOG-PI: Japan Clinical Oncology Group-Prognostic Index; LDH: lactate dehydrogenase..*Statistically significant P value.
seemed necessary for good clinical outcome of HLA class II+ patients. miPD-L1 has been reported in some cancers, but the precise role of miPD-L1 is unclear. It is possible that miPD-L1 suppressed PD-1-expressing tumor cells, but no significant association between miPD-L1 and neoplas- tic PD-1 expression was observed in the present study (data not shown). Further research is required to determine whether there are direct or indirect interactions between HLA class II+ tumor cells and miPD-L1.
Ratner et al. recently reported rapid progression of ATLL after PD-1 blockade therapy.27 They attributed the disease progression to the tumor suppressive role of PD-1 in ATLL. It seems that the ATLL patients included in their study expressed PD-L1 on only <1% or 5% of tumor cells. Our current and previous data suggest that expression of HLA class I/class II and miPD-L1 can predict good clinical outcome in ATLL patients without massive nPD-L1 expression. HLA class I/class II expression might be asso- ciated with the efficacy of PD-1 blockade therapy in ATLL. Although the precise function of miPD-L1 remains to be determined, PD-1 blockade might disrupt tumor immunity associated with miPD-L1 in ATLL.
HLA class II expression on activated normal human T cells is regulated by class II transactivator (CIITA).31 In T- cell malignancies, expression of CIITA also correlates with HLA class II expression.31 In ATLL, CIITA was reported to inhibit the nuclear factor κB pathway activated by the Tax1 oncoprotein of HTLV-1.32 Thus, the favorable clinical prognosis of HLA class II+ ATLL patients may correlate with upregulation of CIITA, which leads to activation of HLA class II expression as well as suppression of the NF- κB signaling pathway.
The rate of HLA class II positivity was low in our study compared to that in the published literature, in which
chronic and smoldering ATLL were reported to show high expression of HLA class II whereas acute type ATLL was described as showing low expression of HLA class II.33 It was suggested that HLA class II expression on ATLL could be associated with progression of chronic ATLL.33 Our study included mostly patients with acute or lymphoma type ATLL. HLA class II expression on acute or lymphoma type ATLL may be correlated with better clinical outcome.
In conclusion, we report, for the first time, that HLA class II expression is a good prognostic marker in ATLL. Both HLA class II and miPD-L1 were required for good clinical outcome. Our results help to understand tumor immunity in ATLL.
Acknowledgments
The authors thank Kazutaka Nakashima, Mayumi Miura, Kanoko Miyazaki, and Chie Kuroki for their technical assistance and collaborators from the following institutions for providing clin- ical data and specimens to the Kyushu Lymphoma Study Group: Department of Medicine and Biosystemic Science, Kyushu University Faculty of Medicine; Department of Hematology, Karatsu Red Cross Hospital; Department of Hematology, Sasebo City General Hospital; Department of Hematology, Atomic Bomb Disease and Hibakusha Medicine Unit, Atomic Bomb Disease Institute, Nagasaki University; and Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University. This work was supported in part by Grants- in-Aid from the Japan Agency for Medical Research and Development (15ck0106015h0002) (MS); the Japan Society for the Promotion of Science (KAKENHI), grant numbers JP26460446 (KO) and JP17K17894 (MT); and the Japan Leukemia Research Fund (General Research Award 2013) (NA). The language and format of this manuscript were edited by Editage (https://www.editage.com).
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