Total population / HLA class I loss / HLA class I downregulation / HLA class I expression / p / FoxP3+ low / FoxP3+ high / p
Total / N 2596 / %
100 / N
298 / %
100 / N
513 / %
100 / N
1080 / %
100 / N
1241 / %
100 / N
1185 / %
100
Age in years
< 40
40-50
50-60
≥60
missing /
1
57
824
1714
0 /
0.0
2.2
31.7
66.0
/ 0
11
94
193
0 / 0.0
3.7
31.5
64.8 / 0
11
160
342
0 / 0.0
2.1
31.2
66.7 / 1
19
332
728
0 / 0.1
1.8
30.7
67.4 / 0.534 / 1
31
387
822
0 / 0.1
2.5
31.2
66.2 / 0
22
385
778
0 / 0.0
1.9
32.5
65.7 / 0.484
pT stage
T1
T2
T3/4
missing / 1173
1247
171
5 / 45.3
48.1
6.6 / 114
165
19
0 / 38.3
55.4
6.4 / 239
240
33
1 / 46.7
46.9
6.4 / 494
521
64
1 / 45.8
48.3
5.9 / 0.152 / 529
625
84
3 / 42.6
50.5
6.8 / 557
555
71
2 / 47.1
46.9
6.0 / 0.095
pN stage
N0
N1
N2/3
missing / 785
1641
168
2 / 30.2
63.2
6.6 / 78
201
19
0 / 26.2
67.4
6.4 / 157
325
31
0 / 30.6
63.4
6.0 / 352
655
72
1 / 32.6
60.6
6.7 / 0.431 / 369
793
78
1 / 29.7
63.9
6.4 / 383
720
81
1 / 32.3
60.8
6.8 / 0.467
Grade
1
2
3
missing / 398
1148
883
167 / 16.4
47.3
36.4 / 52
137
95
14 / 18.3
48.2
33.5 / 91
218
178
26 / 18.7
44.8
36.6 / 117
480
414
69 / 11.6
47.5
40.9 / 0.001 / 215
580
365
81 / 18.5
50.0
31.5 / 146
488
479
72 / 13.1
43.8
43.0 / <0.001
Histology
Ductal
Lobular
mixed
Other
missing / 1936
409
123
106
22 / 75.2
15.9
4.8
4.1 / 229
44
7
13
5 / 78.2
15.0
2.4
4.4 / 388
72
29
22
2 / 75.9
14.1
5.7
4.3 / 861
122
46
45
6 / 80.2
11.4
4.3
4.2 / 0.172 / 892
227
52
55
15 / 72.8
18.5
4.2
4.5 / 929
146
60
44
6 / 78.8
12.4
5.1
3.7 / 0.001
ER status
Positive
Negative
missing / 2543
52
1 / 98.0
2.0 / 295
3
0 / 99.0
1.0 / 503
10
0 / 98.1
1.9 / 1054
26
0 / 97.6
2.4 / 0.315 / 1223
18
0 / 98.5
1.5 / 1153
31
1 / 97.4
2.6 / 0.041
PGR status
Positive
Negative
Missing / 1884
567
145 / 76.9
23.1 / 204
77
17 / 72.6
27.4 / 379
105
29 / 78.3
21.7 / 785
236
59 / 76.9
23.1 / 0.188 / 907
268
66 / 77.2
22.8 / 859
257
69 / 77.0
23.0 / 0.900
HER2 status
Overexpression
No overexpression
Missing / 5
75
2516 / 6.3
93.7 / 0
7
291 / 0
100 / 2
19
492 / 9.5
90.5 / 3
38
1039 / 7.3
92.7 / 0.701 / 1
33
1207 / 2.9
97.1 / 4
40
1141 / 9.1
90.9 / 0.272
Hormone Therapy*
TAM-EXE
EXE
missing / 1298
1298
0 / 50.0
50.0 / 145
153
0 / 48.7
51.3 / 244
269
0 / 47.6
52.4 / 552
528
0 / 51.1
48.9 / 0.382 / 621
620
0 / 50.0
50.0 / 593
592
0 / 50.0
50.0 / 0.968
Surgery type
Mastectomy
Local Excision
missing / 1426
1169
1 / 55.0
45.0
0 / 175
123
0 / 58.7
41.3 / 293
220
0 / 57.1
42.9 / 557
523
0 / 51.6
48.4 / 0.027 / 722
519
0 / 58.2
41.8 / 604
580
1 / 51.0
49.0 / <0.001
Axillary dissection
yes
no
missing / 1996
600
0 / 76.9
23.1 / 236
62
0 / 79.2
20.8 / 395
118
0 / 77.0
23.0 / 814
266
0 / 75.6
24.6 / 0.363 / 965
276
0 / 77.8
22.2 / 886
299
0 / 74.8
25.2 / 0.083
Chemotherapy
yes
no
missing / 771
1824
1 / 29.7
70.3 / 97
201
0 / 32.6
67.4 / 154
359
0 / 30.0
70.0 / 300
779
1 / 27.8
72.2 / 0.246 / 364
876
1 / 29.4
70.6 / 357
828
0 / 30.1
69.9 / 0.678
Radiotherapy
yes
no
missing / 1590
1002
4 / 61.3
38.7 / 170
128
0 / 57.0
43.0 / 290
222
1 / 56.6
43.4 / 681
398
1 / 63.1
36.9 / 0.021 / 719
519
3 / 58.1
41.9 / 765
420
0 / 64.6
35.4 / 0.001

Supplementary Table 1A: Clinicopathologic characteristics of the Dutch TEAM cohort for the expression of classical HLA class I and FoxP3+
*(TAM= tamoxifen; EXE=exemestane)

Total population / HLA-E
low / HLA-E
high / p / HLA-G absence / HLA-G expression / p
Total / N 2596 / %
100 / N
495 / %
100 / N
1419 / %
100 / N
1558 / %
100 / N
484 / %
100
Age in years
< 40
40-50
50-60
≥60
missing /
1
57
824
1714
0 /
0.0
2.2
31.7
66.0
/ 0
16
142
337
0 / 0.0
3.2
28.7
68.1 / 1
24
462
932
0 / 0.1
1.7
32.6
65.7 / 0.087 / 1
35
480
1042
0 / 0.1
2.2
30.8
66.9 / 0
9
162
313
0 / 0.0
1.9
33.5
64.7 / 0.643
pT stage
T1
T2
T3/4
missing / 1173
1247
171
5 / 45.3
48.1
6.6 / 212
243
38
2 / 43.0
49.3
7.7 / 646
693
78
2 / 45.6
48.9
5.5 / 0.176 / 708
750
97
3 / 45.5
48.2
6.2 / 205
247
31
1 / 42.4
51.1
6.4 / 0.487
pN stage
N0
N1
N2/3
missing / 785
1641
168
2 / 30.2
63.2
6.6 / 131
324
40
0 / 26.5
65.5
8.1 / 484
849
85
0 / 34.1
59.8
6.0 / 0.010 / 475
986
96
1 / 30.5
63.3
6.2 / 171
281
31
1 / 35.4
58.2
6.4 / 0.160
Grade
1
2
3
missing / 398
1148
883
167 / 16.4
47.3
36.4 / 95
236
133
31 / 20.5
50.9
28.7 / 160
598
585
76 / 11.9
44.5
43.6 / <0.001 / 236
704
526
92 / 16.1
48.0
35.9 / 51
189
217
27 / 11.2
41.4
47.5 / <0.001
Histology
Ductal
Lobular
mixed
Other
missing / 1936
409
123
106
22 / 75.2
15.9
4.8
4.1 / 345
99
25
22
4 / 70.3
20.2
5.1
4.5 / 1156
144
57
53
9 / 82.0
10.2
4.0
3.8 / <0.001 / 1194
217
76
58
13 / 77.3
14.0
4.9
3.8 / 394
41
18
29
2 / 81.7
8.5
3.7
6.0 / 0.002
ER status
Positive
Negative
Missing / 2543
52
1 / 98.0
2.0 / 488
7
0 / 98.6
1.4 / 1385
33
1 / 97.7
2.3 / 0.222 / 1527
31
0 / 98.0
2.0 / 472
11
1 / 97.7
2.3 / 0.697
PGR status
Positive
Negative
Missing / 1884
567
145 / 76.9
23.1 / 376
94
25 / 80.0
20.0 / 1011
322
86 / 75.8
24.2 / 0.066 / 1135
329
94 / 77.5
22.5 / 348
112
24 / 75.7
24.3 / 0.404
HER2 status
Overexpression
No overexpression
Missing / 5
75
2516 / 6.3
93.7 / 0
15
480 / 0.0
100 / 5
50
1364 / 9.1
90.9 / 0.226 / 5
52
1501 / 8.8
91.2 / 0
16
468 / 0.0
100.0 / 0.220
Hormone Therapy*
TAM-EXE
EXE
missing / 1298
1298
0 / 50.0
50.0 / 241
254
0 / 48.7
51.3 / 719
700
0 / 50.7
49.3 / 0.447 / 762
796
0 / 48.9
51.1 / 238
264
0 / 49.2
50.8 / 0.919
Surgery type
Mastectomy
Local Excision
missing / 1426
1169
1 / 55.0
45.0
0 / 272
223
0 / 54.9
45.1 / 753
665
1 / 53.1
46.9 / 0.478 / 845
713
0 / 54.2
45.8 / 257
226
1 / 53.2
46.8 / 0.692
Axillary dissection
yes
no
missing / 1996
600
0 / 76.9
23.1 / 380
115
0 / 76.8
23.2 / 1060
359
0 / 74.7
25.3 / 0.359 / 1190
368
0 / 76.3
23.6 / 369
115
0 / 76.2
23.8 / 0.949
Chemotherapy
yes
no
missing / 771
1824
1 / 29.7
70.3 / 129
366
0 / 26.1
73.9 / 441
977
1 / 31.1
68.9 / 0.035 / 454
1104
0 / 29.1
70.9 / 148
335
1 / 30.6
69.4 / 0.527
Radiotherapy
yes
no
missing / 1590
1002
4 / 61.3
38.7 / 302
193
0 / 61.0
39.0 / 871
546
2 / 61.5
38.5 / 0.857 / 950
608
0 / 61.0
39.0 / 292
191
1 / 60.5
39.5 / 0.838

Supplementary Table 1B: Clinicopathologic characteristics of the Dutch TEAM cohort for the expression of HLA-E and HLA-G
*(TAM= tamoxifen; EXE=exemestane)

Supplementary Table 2A: Cox univariate and multivariate analysis for RFP, BCSS and OS stratified for endocrine therapy for HLA-I expression of the tumor

Univariate / Multivariate**
Outcome / Hormone therapy* / HLA-I / N / HR / 95%CI / p / HR / 95%CI / p
RFP / EXE / Loss
Downregulation
Expression / 153
269
528 / 1.00
1.180
1.153 / 0.715-1.947
0.731-1.817 / 0.795 / - / - / -
RFP / TAMEXE / Loss
Downregulation
Expression / 145
244
552 / 1.00
1.512
1.353 / 0.919-2.485
0.857-2.137 / 0.265 / - / - / -
BCSS / EXE / Loss
Downregulation
Expression / 153
269
528 / 1.00
0.962
0.993 / 0.527-1.758
0.851-1.696 / 0.988 / - / - / -
BCSS / TAMEXE / Loss
Downregulation
Expression / 145
244
552 / 1.00
1.528
1.215 / 0.838-2.784
0.696-2.120 / 0.323 / - / - / -
OS / EXE / Loss
Downregulation
Expression / 153
269
528 / 1.00
1.090
0.925 / 0.705-1.685
0.620-1.379 / 0.600 / - / - / -
OS / TAMEXE / Loss
Downregulation
Expression / 145
244
552 / 1.00
1.474
1.084 / 0.940-2.312
0.712-1.649 / 0.094 / 1.00
1.390
1.055 / 0.880-2.195
0.689-1.615 / 0.183

*(TAM= tamoxifen; EXE=exemestane)
**Adjusted for age, pT stage, pN stage, tumor grade, histology, surgery type, chemotherapy and radiotherapy

Supplementary Table 2B: Cox univariate and multivariate analysis for RFP, BCSS and OS stratified for endocrine therapy for HLA-E expression of the tumor

Univariate / Multivariate**
Outcome / Hormone therapy* / HLA-E / N / HR / 95%CI / p / HR / 95%CI / p
RFP / EXE / Low
High / 254
700 / 1.00
1.049 / 0.734-1.500 / 0.793 / - / - / -
RFP / TAMEXE / Low
High / 241
719 / 1.00
1.345 / 0.942-1.919 / 0.103 / - / - / -
BCSS / EXE / Low
High / 254
700 / 1.00
1.171 / 0.736-1.862 / 0.505 / - / - / -
BCSS / TAMEXE / Low
High / 241
719 / 1.00
1.459 / 0.929-2.291 / 0.101 / - / - / -
OS / EXE / Low
High / 254
700 / 1.00
0.921 / 0.666-1.274 / 0.621 / - / - / -
OS / TAMEXE / Low
High / 241
719 / 1.00
1.027 / 0.750-1.406 / 0.869 / - / - / -

*(TAM= tamoxifen; EXE=exemestane)
**Adjusted for age, pT stage, pN stage, tumor grade, histology, surgery type, chemotherapy and radiotherapy

Supplementary Table 2C: Cox univariate and multivariate analysis for RFP, BCSS and OS stratified for endocrine therapy for HLA-G expression of the tumor

Univariate / Multivariate**
Outcome / Hormone therapy* / HLA-G / N / HR / 95%CI / p / HR / 95%CI / p
RFP / EXE / Absence
Presence / 796
246 / 1.00
0.960 / 0.676-1.364 / 0.821 / - / - / -
RFP / TAMEXE / Absence
Presence / 762
238 / 1.00
0.876 / 0.625-1.227 / 0.441 / - / - / -
BCSS / EXE / Absence
Presence / 796
246 / 1.00
0.988 / 0.641-1.526 / 0.958 / - / - / -
BCSS / TAMEXE / Absence
Presence / 762
238 / 1.00
0.698 / 0.451-1.082 / 0.108 / - / - / -
OS / EXE / Absence
Presence / 796
246 / 1.00
0.786 / 0.560-1.104 / 0.165 / - / - / -
OS / TAMEXE / Absence
Presence / 762
238 / 1.00
0.830 / 0.601-1.144 / 0.255 / - / - / -

*(TAM= tamoxifen; EXE=exemestane)
**Adjusted for age, pT stage, pN stage, tumor grade, histology, surgery type, chemotherapy and radiotherapy

Supplementary Table 2D: Cox univariate and multivariate analysis for RFP, BCSS and OS stratified for endocrine therapy for FoxP3+ expression

Univariate / Multivariate**
Outcome / Hormone therapy* / FoxP3+ / N / HR / 95%CI / p / HR / 95%CI / p / Interaction p
RFP / EXE / Low
High / 621
592 / 1.00
0.843 / 0.637-1.114 / 0.230 / - / - / - / -
RFP / TAMEXE / Low
High / 620
593 / 1.00
0.979 / 0.755-1.270 / 0.874 / - / - / -
BCSS / EXE / Low
High / 621
592 / 1.00
0.944 / 0.664-1.340 / 0.745 / - / - / - / -
BCSS / TAMEXE / Low
High / 620
593 / 1.00
0.808 / 0.585-1.117 / 0.197 / - / - / -
OS / EXE / Low
High / 621
592 / 1.00
0.821 / 0.633-1.065 / 0.138 / - / - / - / <0.001
OS / TAMEXE / Low
High / 620
593 / 1.00
0.752 / 0.586-0.966 / 0.026 / 1.00
0.729 / 0.560-0.949 / 0.019

*(TAM= tamoxifen; EXE=exemestane)
**Adjusted for age, pT stage, pN stage, tumor grade, histology, surgery type, chemotherapy and radiotherapy

Supplementary Table 3: composition of tumor immune subtypes based on the regression coefficient of the mono-markers in the relapse free period.

Tumor immune subtype category / HLA-I / HLA-G / HLA-E / FoxP3+ / N / Regression coefficient range
High / Loss / Negative/Positive / Negative / Low/High / 152 / (-0.485) – (-0.108)
(1st tertile)
Loss / Positive / Positive / Low/High / 6
Down-regulation / Positive / Negative / Low/High / 14
Expression / Negative/Positive / Negative / Low/High / 116
Expression / Positive / Positive / High / 213
Intermediate / Loss / Negative / Positive / Low/High / 100 / (-0.086 – (0.011)
(2nd tertile)
Down-regulation / Negative / Negative / Low/High / 127
Expression / Positive / Positive / Low / 91
Low / Down-regulation / Negative/Positive / Positive / Low/High / 288 / (0.065) – (0.287)
(3rd tertile)
Expression / Negative / Positive / Low/High / 529