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Figure legends
Fig. 1 Characterization of TLS in PDAC. a Representative images of H&E-stained
sections were obtained from resected PDAC. The dotted line indicates the margin
of the tumor, and the black arrow indicates the TLS beside the tumor (left panel).
TLS within the tumor is shown, and black arrowheads indicate cancer cells (right
panel). b & c Components and proportions of immune cells within TLS. In the
IHC analysis, the TLSs were composed of T cells (CD4, CD8, CD45RO, and
FOXP3), B cells (CD20), and macrophages (CD68). d The association between
the presence of TLS and tumor characteristics (pTNM stage, pT stage, and
histological grade). Statistical significance was set at P < 0.05. Original
magnification (a, 40×; b, 200×). Scale bars, 200 μm (a); 50 μm (b). H&E,
haematoxylin and eosin; IHC, immunohistochemistry; PDAC, pancreatic ductal
adenocarcinoma; TLS, tertiary lymphoid structure
Fig. 2 CSS of the PDAC patients according to the presence or absence of TLS.
The CSS of PDAC patients according to the presence or absence of TLS was
investigated. The differences of the CSS in adjuvant chemotherapy among the
groups treated with S-1, gemcitabine, and non-treated groups according to the
47
presence or absence of TLS were also examined. a All patients b TLS-present,
and c TLS-absent patients. The CSS curves were estimated using the KaplanMeier method, and the significant differences between the two groups were
evaluated using a log-rank test. The number of patients at risk is shown in the
CSS curves. CSS, cancer-specific survival; PDAC, pancreatic ductal
adenocarcinoma; TLS, tertiary lymphoid structure
Supplementary Fig. 1 Representative immunohistochemistry images. a Typical
images of high or low levels of CD4+, CD8+, CD45RO+ and FOXP3+ TILs. b
Typical images of presence or absence of CD274 (PD-L1) expression. c Typical
images of intact or altered (lost or over expression) of protein expression of TP53,
CDKN2A and SMAD4. Original magnification (a-c, 200×). Scale bars, 50 μm (ac). PDL1, Programmed death-ligand 1; TILs, tumor infiltrating lymphocytes
Supplementary Fig. 2 CSS of PDAC patients according to the intratumoral TLS
and peritumoral TLS. Intratumoral TLSs were detected within and around the
tumor; peritumoral TLSs were detected only around the tumor. The CSS curves
were estimated using the Kaplan-Meier method, and the significant differences
48
between the two groups were evaluated using a log-rank test. The number of
patients at risk is shown in the CSS curves. CSS, cancer-specific survival; PDAC,
pancreatic ductal adenocarcinoma; TLS, tertiary lymphoid structure
Supplementary Fig. 3 CSS of PDAC patients according to the level of NLR or
extent of CD8+ TILs. The CSS of PDAC patients according to high or low NLR
were investigated. The differences of the CSS in adjuvant chemotherapy among
the groups treated with S-1, gemcitabine, and non-treated groups according to
the high or low NLR were also examined. a All patients b Patients with low
NLR c Patients with high NLR. The CSS of PDAC according to the high or low
levels of CD8+ TILs were investigated. The differences of the CSS in adjuvant
chemotherapy among the groups treated with S-1, gemcitabine, and non-treated
groups according to the high or low levels of CD8+ TILs were also examined. d
All patients e Patients with high levels of CD8+ TILs f Patients with low levels
of CD8+ TILs. The CSS curves were estimated using the Kaplan-Meier method,
and the significant differences between the two groups were evaluated by a logrank test. The number of patients at risk is shown in the CSS curves. CSS,
cancer-specific survival; NLR, neutrophil-to lymphocyte ratio; PDAC, pancreatic
49
ductal adenocarcinoma; TILs, tumor infiltrating lymphocytes
Supplementary Fig. 4 In situ hybridization for IFN-gamma and IL-2, and
apoptosis assay. a Typical images of IFN-gamma and IL-2 expression in TLSpresent and absent patients. IFN-gamma-positive cells and IL-2-positive
cells show distinct red staining. b The expression levels of IFN-gamma or IL-2
per cm2 in TLS-present patients (n=5) and TLS-absent patients (n=5) were
counted. Mean ± SD (bars). *, P < 0.05. c Double immunohistochemistry-in situ
hybridization. To distinguish between IHC of CD4+ and CD8+ T cells (brown) and
ISH of IFN-gamma (pink) more clearly, brown is changed to green using color
replacement tools of Photoshop. IFN-gamma mRNA (pink arrowhead) was
localized to CD4+ and CD8+ T cells (green). d TUNEL assays were performed 7
days after the addition of IFN-gamma (100 units/mL), IL-2 (500 units/ml), 5-FU
(0.05 mg/mL), and their combination to detect the apoptotic cells. TUNEL analysis
showed a significant difference in cell numbers at day 7 between the combination
therapy group and other treatment groups. Mean ± SD (bars). **, P < 0.001, ***,
P < 0.01. Original magnification (a, c, 400×). Scale bars, 20 μm. IFN, interferon;
IL, interleukin; PDAC, pancreatic ductal adenocarcinoma; SD, standard
50
deviation; TLS, tertiary lymphoid structure
51
Table 1. Patient’s characteristics according to presence or absence of TLS in PDAC
Characteristics
Age (years), Median (range)
BMI (kg/m2), Median (range)
Sex
Male
Female
Family history of PDAC
Present
Absent
Alcohol consumption
< 50 (g/day)
≥ 50 (g/day)
History of smoking
Present
Absent
Diabetes mellitus
Present
Absent
CA19-9
< 37 (U/ml)
≥ 37 (U/ml)
CEA
< 5 (ng/ml)
≥ 5 (ng/ml)
Pathological Stagea
Ia/Ib
IIa/IIb
III
Neoadjuvant chemotherapy
Present
Absent
Adjuvant chemotherapy
Present
Absent
Histology grade
Well/Moderate
Poorly
Residual tumor status
R0
R1
KRAS mutation
Present
Absent
TP53 alteration
Present
Absent
CDKN2A alteration
Present
Absent
SMAD4 alteration
Present
Absent
CD274 expression
Positive
Negative
All patients (N=162)
69 (40-85)
21.0 (14.3-33.2)
Present (N=112)
70 (40-85)
21.0 (14.3-32.3)
TLS
Absent (N=50)
69 (48-82)
20.7 (16.5-33.2)
90 (55.6%)
72 (44.4%)
64 (57.1%)
48 (42.9%)
26 (52.0%)
24 (48.0%)
14 (8.6%)
148 (91.4%)
11 (9.8%)
101 (90.2%)
3 (6.0%)
47 (94.0%)
146 (90.1%)
16 (9.9%)
98 (87.5%)
14 (12.5%)
48 (96.0%)
2 (4.0%)
78 (48.1%)
84 (51.9%)
61 (54.5%)
51 (45.5%)
17 (34.0%)
33 (66.0%)
64 (39.5%)
98 (60.5%)
44 (39.3%)
68 (60.7%)
20 (40.0%)
30 (60.0%)
40 (24.7%)
122 (75.3%)
34 (30.4%)
78 (69.6%)
6 (12.0%)
44 (88.0%)
116 (71.6%)
46 (28.4%)
79 (70.5%)
33 (29.5%)
37 (74.0%)
13 (26.0%)
35 (21.6%)
89 (54.9%)
38 (23.5%)
27 (24.1%)
62 (55.4%)
23 (20.5%)
8 (16.0%)
27 (54.0%)
15 (30.0%)
18 (11.1%)
144 (88.9%)
13 (11.6%)
99 (88.4%)
5 (10.0%)
45 (90.0%)
117 (72.2%)
45 (27.8%)
83 (74.1%)
29 (25.9%)
34 (68.0%)
16 (32.0%)
143 (88.3%)
19 (11.7%)
99 (88.4%)
13 (11.6%)
44 (88.0%)
6 (12.0%)
118 (72.8%)
44 (27.2%)
84 (75.0%)
28 (25.0%)
34 (68.0%)
16 (32.0%)
150 (92.6%)
12 (7.4%)
104 (92.9%)
8 (7.1%)
46 (92.0%)
4 (8.0%)
111 (68.5%)
51 (31.5%)
76 (67.9%)
36 (32.1%)
35 (70.0%)
15 (30.0%)
104 (64.2%)
58 (35.8%)
68 (60.7%)
44 (39.3%)
36 (72.0%)
14 (28.0%)
62 (38.3%)
100 (61.7%)
39 (34.8%)
73 (65.2%)
23 (46.0%)
27 (54.0%)
23 (14.2%)
139 (85.8%)
9 (8.0%)
103 (92.0%)
14 (28.0%)
36 (72.0%)
P value
0.66
0.92
0.61
0.55
0.15
0.02
0.99
0.02
0.71
0.30
0.99
0.45
0.99
0.44
0.99
0.86
0.21
0.22
0.002
(%) indicates the proportion of cases with a specific clinical, pathological, or tumor
molecular characteristic according to the presence or absence of TLS.
a Pathological stage was diagnosed based on TNM Classification of Malignant Tumors,
8th Edition. BMI, body mass index; CA19-9, carbohydrate antigen 19-9; CEA,
carcinoembryonic antigen; PDAC, pancreatic ductal adenocarcinoma; PD-L1,
programmed cell death ligand-1; TLS, tertiary lymphoid structure.
Table 2. The association of TLS with TILs in PDAC
No. of
Cases
TLS
No. of cases
with high levels of
CD4+ TILs
162
80 (49.4%)
Absence
50
14 (28.0%)
1 (reference)
1 (reference)
1 (reference)
Presence
112
66 (58.9%)
3.69 (1.82-7.80)
4.21 (1.93-9.74)
3.50 (1.65-7.80)
0.0002
0.0002
0.001
P value
TLS
No. of
Cases
162
Absence
50
9 (18.0%)
1 (reference)
1 (reference)
1 (reference)
Presence
112
72 (64.3%)
8.20 (3.76-19.6)
9.15 (3.98-23.1)
11.0 (4.57-29.7)
<0.0001
<0.0001
<0.0001
High levels of CD45RO+ TILs
Univariate
Multivariate
Multivariate
OR (95%CI)
ORa (95%CI)
ORb (95%CI)
No. of
Cases
162
No. of cases
with high levels of
CD45RO+ TILs
81 (50.0%)
Absence
50
17 (34.0%)
1 (reference)
1 (reference)
1 (reference)
Presence
112
64 (57.1%)
2.59 (1.31-5.27)
2.51 (1.19-5.46)
2.65 (1.25-5.80)
0.006
0.02
0.01
P value
TLS
High levels of CD8+ TILs
Univariate
Multivariate
Multivariate
OR (95%CI)
ORa (95%CI)
ORb (95%CI)
No. of cases
with high levels of
CD8+ TILs
81 (50.0%)
P value
TLS
High levels of CD4+ TILs
Univariate
Multivariate
Multivariate
OR (95%CI)
ORa (95%CI)
ORb (95%CI)
High levels of FOXP3+ TILs
Univariate
Multivariate
Multivariate
OR (95%CI)
ORa (95%CI)
ORb (95%CI)
No. of
Cases
162
No. of cases
with high levels of
FOXP3+ TILs
76 (46.9%)
Absence
50
23 (46.0%)
1 (reference)
1 (reference)
1 (reference)
Presence
112
53 (47.3%)
1.05 (0.54-2.07)
0.86 (0.40-1.81)
0.80 (0.45-1.83)
0.88
0.68
0.80
P value
Lymphocyte counts were divided into high and low group by the median split. The median of CD4+,
CD8+, CD45RO+ and FOXP3+ T cells are 48, 140, 110 and 33 count/mm2, respectively.
a The odds ratio was initially adjusted for age, sex, BMI, amount of alcohol consumption, family
history of pancreatic cancer, history of smoking, diabetes mellitus, serum CA19-9, serum CEA.
b The odds ratio was initially adjusted for stage, histology, adjuvant, neo-adjuvant, residual tumor
status, gene alterations (KRAS, TP53, CDKN2A, SMAD4).
OR, odds ratio; PDAC, pancreatic ductal adenocarcinoma; TILs, tumor-infiltrating lymphocytes; TLS,
tertiary lymphoid structure.
Table 3. The association of TLS with serum ALC, ANC and NLR in PDAC
TLS
No. of cases with
high levels of ALC
81 (50.0%)
Univariate
OR (95%CI)
Absence
50
17 (34.0%)
1 (reference)
1 (reference)
1 (reference)
Presence
112
64 (57.1%)
2.59 (1.31-5.27)
2.84 (1.33-6.28)
2.46 (1.21-5.12)
0.006
0.007
0.01
P value
TLS
High levels of serum ANC
Univariate
Multivariate
Multivariate
OR (95%CI)
ORa (95%CI)
ORb (95%CI)
No. of
cases
162
No. of cases with
high levels of ANC
80 (49.4%)
Absence
50
24 (48.0%)
1 (reference)
1 (reference)
1 (reference)
Presence
112
56 (50.0%)
1.08 (0.56-2.12)
1.33 (0.64-2.75)
1.11 (0.54-2.30)
0.81
0.44
0.78
Multivariate
ORb (95%CI)
P value
TLS
High levels of serum ALC
Multivariate
Multivariate
ORa (95%CI)
ORb (95%CI)
No. of
cases
162
No. of
cases
162
No. of cases with
low levels of NLR
80 (49.4 %)
Univariate
OR (95%CI)
Low levels of NLR
Multivariate
ORa (95%CI)
Absence
50
15 (30.0%)
1 (reference)
1 (reference)
1 (reference)
Presence
112
65 (58.0%)
3.23 (1.61-6.72)
3.21 (1.51-7.10)
3.15 (1.53-6.72)
0.0009
0.002
0.002
P value
ALC and ANC counts and NLR were divided into high and low categories by the median split.
The median of ALC and ANC were 1522 and 3251 count/mm2, respectively. The median of NLR
was 2.1.
a The odds ratio was initially adjusted for age, sex, BMI, amount of alcohol consumption, family
history of pancreatic cancer, history of smoking, diabetes mellitus, serum CA19-9, serum CEA.
b The odds ratio was initially adjusted for stage, histology, adjuvant, neo-adjuvant, residual
tumor status, gene alterations (KRAS, TP53, CDKN2A, SMAD4).
ALC, absolute lymphocyte counts; ANC, absolute neutrophil counts; NLR, neutrophil-to
lymphocyte ratio; OR, odds ratio; PDAC, pancreatic ductal adenocarcinoma; TLS, tertiary
lymphoid structure.
Table 4. Presence of TLS and cancer specific mortality in PDAC
Pancreatic cancer specific mortality
Univariate
Multivariate
Multivariate
HR (95%CI)
HRa (95%CI)
HRb (95%CI)
All cases
No. of
cases
162
No. of
events
107
TLS absence
50
43
1 (reference)
1 (reference)
TLS presence
112
64
0.40 (0.27-0.59)
0.40 (0.26-0.61)
<0.0001
<0.0001
<0.0001
1 (reference)
1 (reference)
P value
Pathological
stage IIb-IIIc
119
88
TLS absence
40
37
1 (reference)
TLS presence
79
51
0.34 (0.22-0.53)
P value
<0.0001
0.35 (0.22-0.56)
<0.0001
1 (reference)
0.37 (0.25-0.56)
0.33 (0.21-0.52)
<0.0001
The hazard ratio was initially adjusted for age, sex, BMI, amount of alcohol consumption, family
history of pancreatic cancer, history of smoking, diabetes mellitus, serum CA19-9, serum CEA.
b The hazard ratio was initially adjusted for stage, histology, adjuvant, neo-adjuvant, residual tumor
status, gene alterations (KRAS, TP53, CDKN2A, SMAD4).
c Pathological stage was diagnosed based on TNM Classification of Malignant Tumors, 8th Edition.
HR, hazard ratio; PDAC, pancreatic ductal adenocarcinoma; TLS, tertiary lymphoid structure.
Table 5. Adjuvant chemotherapy and patient mortality in PDAC
TLS
Presence
TLS
Absence
Pancreatic cancer specific mortality
Univariate
Multivariate
P value
HR (95%CI)
HR (95%CI)
1 (reference)
1 (reference)
Adjuvant
chemotherapy
Absent
No. of
cases
29
No. of
events
19
S-1
60
27
0.43 (0.24-0.79)
0.007
0.51 (0.26-0.97)
0.04
GEM
Absent
23
16
18
15
0.66 (0.34-1.28)
1 (reference)
0.21
0.60 (0.29-1.26)
1 (reference)
0.18
S-1
14
12
0.66 (0.30-1.42)
0.28
0.61 (0.27-1.37)
0.23
GEM
20
16
0.71 (0.35-1.46)
0.35
0.67 (0.27-1.37)
0.30
P value
The hazard ratio was initially adjusted for age, BMI, history of smoking, residual tumor status. BMI,
body mass index; GEM, gemcitabine; HR, hazard ratio; PDAC, pancreatic ductal adenocarcinoma;
TLS, tertiary lymphoid structure.
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