Serum levels of soluble programmed death protein 1 (sPD-1) and soluble programmed death ligand 1 (sPD-L1) in advanced pancreatic cancer

Figures & data

Figure 1. Correlation of sPD-1 and sPD-L1 levels in individual patients with advanced pancreatic cancer (n = 41).

Table 1. Prognostic relevance of sPD-1 and sPD-L1.

	Univariate analysis			Multivariate analysis
Parameter	HR	95% CI	p value	HR	95% CI	p value
Age > 65 y	1.13	[0.56–2.28]	0.74
ECOG > 1	1.48	[0.20–10.92]	0.70
CA-19–9 > 1,000 U/mL	1.96	[0.98–3.9]	0.06	2.29	[1.07–4.9]	< 0.05
CRP [mg/dL]	1.06	[1.01–1.11]	< 0.05	1.08	[1.02–1.13]	< 0.01
sPD-1 [ng/mL]	0.74	[0.44–1.24]	0.25	0.74	[0.01–489.78]	0.93
sPD-L1 [ng/mL]	0.23	[0.01–13.52]	0.48	0.90	[0.37–2.20]	0.82

Abbreviations: CA 19–9: carbohydrate antigen 19–9; CEA: carcinoembryonic antigen; CI, confidence interval; CRP: C-reactive protein; ECOG: Eastern Cooperative Oncology Group performance status; HR, hazard ratio; sPD-1, soluble programmed death protein 1; sPD-L1, soluble programmed death-ligand 1.

CRP, sPD-1 and sPD-L1 were considered as continuous variables.

Table 2A. Clinical characteristics of patients with high vs. low levels of sPD-1.

	Low sPD-1 (n = 20)	High sPD-1 (n = 21)
Age years (Median)	66.05 [44–81]	67.10 [38–77]
CRP mg/dL (Median, Range)	1.6 [0.1–32.8]	1.4 [0.1–14.6]
Leukocytes G/L (Median, Range)	7.3 [4.5–18.0]	7.2 [4.3–18.0]
CA-19–9 U/mL (Median, Range)	364 [2.6–122 000]	1455 [2.6–422 000]
CEA ng/mL (Median, Range)	4.3 [0.7–122]	10.2 [0.2–432]
Stage
Locally advanced pancreatic cancer	2	4
Metastatic pancreatic cancer	18	17
Performance status
ECOG 0	10	10
ECOG 1	9	9
ECOG 2	0	1
ECOG 3	1	0
ECOG missing	0	1
Median overall survival (months)	9.53 [95% CI: 5.06–13.99]	11.93 [95% CI: 6.13–17.72]

Abbreviations: CA 19–9: carbohydrate antigen 19–9; CEA: carcinoembryonic antigen; CI, confidence interval; CRP: C-reactive protein; ECOG: Eastern Cooperative Oncology Group performance status; sPD-1, soluble programmed death protein 1; sPD-L1, soluble programmed death-ligand 1.

Table 2B. Clinical characteristics of patients with high vs. low levels of sPD-L1.

	Low sPD-L1 (n = 20)	High sPD-L1 (n = 21)
Age years (Median, Range)	66.05 [41–81]	67.10 [38–77]
CRP mg/dL (Median, Range)	0.9 [0.1–14.6]	1.6 [0.1–32.8]
Leukocytes G/L (Median, Range)	7.2 [4.5–18.0]	7.4 [4.3–18.0]
CA-19–9 U/mL (Median, Range)	353 [2.6–16 257]	1466 [2.6–422 000]
CEA ng/mL (Median, Range)	4.0 [0.7–59.8]	9.0 [0.2–432]
Stage
Locally advanced pancreatic cancer	3	3
Metastatic pancreatic cancer	17	18
Performance status
ECOG 0	10	10
ECOG 1	9	9
ECOG 2	0	1
ECOG 3	1	0
ECOG missing	0	1
Median overall survival (months)	9.53 [95% CI: 5.06–13.99]	11.92 [95% CI: 6.41–17.44]

Abbreviations: CA 19–9: carbohydrate antigen 19–9; CEA: carcinoembryonic antigen; CI, confidence interval; CRP: C-reactive protein; ECOG: Eastern Cooperative Oncology Group performance status; sPD-1, soluble programmed death protein 1; sPD-L1, soluble programmed death-ligand 1.

Figure 2. Overall survival for patients with high vs. low levels of sPD-1 or sPD-L1 (n = 41).

Figure 3. (A) Distribution of sPD-1 (left figure) and sPD-L1 (right figure) in patients with normal vs. elevated CRP. Differences in mean were tested using a Student's t-test, differences in distribution pattern were tested using an F-test. (B) Immunohistochemical staining of PD-L1 in controls (A, B) and exemplary pancreatic cancer tissue (C, D). Magnification = × 200. Scale bars indicate 50 µm. (C) Correlation analysis of sPD-L1 levels with tumoral CD3+ T cell infiltration (left figure) and tumoral PD-L1 expression (right figure) in advanced pancreatic cancer patients; Left figure: Correlation of sPD-L1 with tumoral CD3+ T cell infiltration (tCD3 count), differences between groups were tested using an F-test. Right figure: Correlation of sPD-L1 levels with tumoral PD-L1 expression, Pearson coefficient analysis was used to test for a potential correlation.

Table 3. Correlation of sPD-L1 levels with tumoral PD-L1 expression and tumoral CD3+ T cell infiltration in advanced pancreatic cancer.

Patient number	sPD-L1 level [ng/mL]	% PD-L1+ pancreatic cancer cells	Tumor infiltration by CD3+ T cells	Type of tumor tissue	Δ [days] from acquisition of tissue sample to blood draw
1	0.013	0	1	liver metastasis	23
2	0.007	no remaining tumor tissue	—	—	—
3	0.012	5	1	peritoneal metastasis	21
4	0.138	external pathology	—	—	—
5	0.007	10	1	liver metastasis	7
6	0.007	external pathology	—	—	—
7	0.007	0	2	peritoneal metastasis	21
8	0.007	30	1	liver metastasis	5
9	0.007	0	2	primary tumor	28
10	0.007	external pathology	—	—	—
11	0.029	0	0	liver metastasis	4
12	0.007	0	1	liver metastasis	12
13	0.007	external pathology	—	—	—
14	0.119	0	1	cutaneous metastasis	16
15	0.021	0	1	liver metastasis	5
16	0.039	0	1	primary tumor after neoadjuvant treatment	−317
17	0.007	0	2	primary tumor	17
18	0.007	20	0	liver metastasis	12
19	0.043	30	1	liver metastasis	–7
20	0.009	0	1	primary tumor	12
21	0.012	0	1	primary tumor	−2
22	0.007	0	2	liver metastasis	26
23	0.632	external pathology	—		—
24	0.007	0	1	liver metastasis	0
25	0.007	external pathology	—	—	—
26	0.078	30	2	primary tumor	77
27	0.007	60	2	primary tumor after neoadjuvant treatment	−210
28	0.031	external pathology	—	—	—
29	0.047	0	2	liver metastasis	19
30	0.007	no remaining tumor tissue	—	—	—
31	0.222	0	2	primary tumor	5
32	0.013	0	1	liver metastasis	6
33	0.008	no remaining tumor tissue	—	—	—
34	0.015	20	1	liver metastasis	11
35	0.067	0	2	primary tumor	23
36	0.008	20	0	liver metastasis	−2
37	0.026	0	1	primary tumor	14
38	0.178	external pathology	—	—	—
39	0.012	0	1	primary tumor	49
40	0.019	0	1	primary tumor	1,205
41	0.093	0	2	primary tumor	38

Scoring for tumor infiltration by CD3± T cells: 2 = high number of peritumoral CD3± T cells, 1 = intermediate number of peritumoral CD3± T cells, 0 = low number CD3± T cells. Only CD3± T cells in immediate adjacency to malignant cells were counted.

Abbreviations: sPD-L1, soluble programmed death-ligand 1.