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M. Takeuchi et al.
study. Recently, the importance of CD4+ T cells and HLA class II-restricted neoantigens has been focused on in can- cer immunology. It has been suggested that CD4+ type 1 helper T cells can upregulate HLA class II expression on tumor cells by producing cytokines and that they can kill tumor cells directly, independently of other immune cells.30 Thus, CD4+ non-neoplastic T cells may also con- tribute to the improved prognosis of HLA class II+ ATLL patients. In addition, CD4+ helper T cells can help CD8+ T cells in tumor immunity.30 Thus, HLA class II expression
A
may be necessary for CD8+ T cells to attack HLA class I+ tumor cells.
HLA class II expression was also reported to be a good prognostic factor in diffuse large B-cell lymphoma,22 a malignancy derived from B cells. Thus, diffuse large B-cell lymphoma originally has active HLA class II, which can present neoantigens, suggesting that loss of HLA class II on diffuse large B-cell lymphoma disrupts the interaction with CD4+ T cells.
In our study, PD-L1-expressing stromal cells (miPD-L1+)
B
Figure 4. Overall survival associated with HLA class II and programmed death ligand-1 expression. (A) Patients were stratified into four groups according to the expression of human leukocyte antigen (HLA) class II and programmed death ligand-1 on neoplastic cells (nPD-L1). The differences in survival are depicted in the Kaplan–Meier plot (P<0.0001; log-rank test). (B) The patients were divided into four groups according to the expression of HLA class II and programmed death lig- and-1 on microenvironmental cells (miPD-L1). Kaplan–Meier plots reveal the differences among the groups (P<0.0001; log-rank test).
Table 3. Clinicopathological comparison according to HLA class II expression.
HLA class II+ (n=44) % HLA class II– (n=88) %
P
0.0697
0.3515
0.5387 0.5382 -
-
0.3297 0.5654 0.2601 0.1387 0.5788
0.1624 0.7731 0.4205 0.1049
0.0421*
0.0165* 0.1655 0.1266 0.0020*
Age, mean (range), years
Sex, male/female
Shimoyama classification Acute type
Lymphoma type Smoldering type Chronic type
PS score 2-4
IPI high or high-intermediate JCOG-PI high
Ann Arbor stage III, IV Elevated LDH
Treatment Chemotherapy Radiation Transplantation No treatment
CR/CR(u)
Immunohistochemistry HLA class Im+β2M m+ nPD-L1+
miPD-L1+
PD-1+ TIL (/hpf), average (range)
65.5 (35-80) 68.5 (40-90)
28/16 47/41
19/35 54.3 34/73 46.6 15/35 42.8 37/73 50.7 1/35 2.9 2/73 2.7 0/35 0.0 0/73 0.0
12/44 27.3 31/85 36.5 25/43 58.1 53/83 63.9 14/44 31.8 36/85 42.4 34/44 77.3 77/88 87.5 27/44 61.4 49/88 55.7
36/44 81.8 79/87 90.8 4/43 9.3 10/86 11.6 4/43 9.3 13/86 15.1 7/44 15.9 5/86 5.8
15/36 41.7 17/79 21.5
22/39 56.4 26/81 32.1 5/44 11.4 4/86 4.7 32/44 72.7 51/88 58.0
3.95 (0-37.4) 1.83 (0-38.4)
HLA: human leukocyte antigen; PS: Performance Status; IPI: International Prognostic Index; JCOG-PI; Japan Clinical Oncology - Prognostic Index; LDH: lactate dehydrogenase; CR: complete response; CR(u),: complete response (unconfirmed); β2M: β2 microglobulin; nPD-L1: neoplastic programmed death ligand-1; miPD-L1: microenvironmental pro- grammed death ligand-1; PD-1: programmed death-1; TIL: tumor infiltrating cells; hpf: high power field. *Statistically significant P value.
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haematologica | 2019; 104(8)