Clinical significance of programmed cell death-ligand expression in small bowel adenocarcinoma is determined by the tumor microenvironment

doi:10.3748/wjg.v29.i40.5566

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Oct 28, 2023 (publication date) through Jun 19, 2024

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World Journal of Gastroenterology

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Retrospective Study

World J Gastroenterol. Oct 28, 2023; 29(40): 5566-5581
Published online Oct 28, 2023. doi: 10.3748/wjg.v29.i40.5566

Table 1 Clinicopathological data of patients with small bowel adenocarcinoma

	No. of cases (%)
Age
≤ 68	27 (54.0)
> 68	23 (46.0)
Sex
Female	15 (30.0)
Male	35 (70.0)
Site
Duodenum and jejunum	45 (90.0)
Ileum	5 (10.0)
Histology
WD, MD	41 (82.0)
PD, Muc	9 (18.0)
Depth of invasion
pT1-2	14 (28.0)
pT3-4	36 (72.0)
Lymph node metastasis
Absence	27 (54.0)
Presence	23 (46.0)
Distant metastasis
Absence	37 (74.0)
Presence	13 (26.0)
Peritoneal seeding
Absence	40 (80.0)
Presence	10 (20.0)
Chemotherapy
Absence	27 (54.0)
Presence	23 (46.0)
TNM stage
I	14 (28.0)
II	13 (26.0)
III	10 (20.0)
IV	13 (26.0)

WD: Well differentiated; MD: Moderately differentiated; PD: Poorly differentiated; Muc: Mucinous adenocarcinoma.

Table 2 Clinicopathological correlation of programmed cell death-ligand 1 and programmed cell death-ligand 2 expression

	No.	T-PD-L1		I-PD-L1		PD-L1 CPS ≥ 10		T-PD-L2		I-PD-L2		PD-L2 CPS ≥ 10
	No.	N (%)	P value	N (%)	P value	N (%)	P value	N (%)	P value	N (%)	P value	N (%)	P value
Age
≤ 68	27	10 (37.0)	NS	16 (59.3)	NS	14 (51.9)	NS	12 (44.4)	NS	14 (51.9)	NS	19 (70.4)	0.027
> 68	23	7 (30.4)		11 (47.8)		11 (47.8)		5 (21.7)		7 (30.4)		9 (39.1)
Sex
Female	15	4 (26.7)	NS	7 (46.7)	NS	7 (46.7)	NS	6 (40.0)	NS	8 (53.3)	NS	8 (53.3)	NS
Male	35	13 (37.1)		20 (57.1)		18 (51.4)		11 (31.4)		13 (37.1)		20 (57.1)
Site
Duodenum and jejunum	45	16 (35.6)	NS	25 (55.6)	NS	24 (53.3)	NS	16 (35.6)	NS	20 (44.4)	NS	26 (57.8)	NS
Ileum	5	1 (20.0)		2 (40.0)		1 (20.0)		1 (20.0)		1 (20.0)		2 (40.0)
Histology
WD, MD	41	13 (31.7)	NS	24 (58.5)	NS	21 (51.2)	NS	17 (41.5)	0.015	19 (46.3)	NS	26 (63.4)	0.030
PD, Muc	9	4 (44.4)		3 (33.3)		4 (44.4)		0 (0.0)		2 (22.2)		2 (22.2)
Depth of invasion
pT1-2	14	0 (0.0)	0.001	4 (28.6)	0.024	2 (14.3)	0.002	5 (35.7)	NS	6 (42.9)	NS	6 (42.9)	0.068
pT3-4	36	17 (47.2)		23 (63.9)		23 (63.9)		12 (33.3)		15 (41.7)		22 (61.1)
Lymph node metastasis
Absence	27	8 (29.6)	NS	16 (59.3)	NS	13 (48.1)	NS	8 (29.6)	NS	13 (48.1)	NS	15 (55.6)	NS
Presence	23	9 (39.1)		11 (47.8)		12 (52.2)		9 (39.1)		8 (34.8)		13 (56.5)
Distant metastasis
Absence	37	12 (32.4)	NS	22 (59.5)	NS	20 (54.1)	NS	13 (35.1)	NS	18 (48.6)	NS	23 (62.2)	0.095
Presence	13	5 (38.5)		5 (38.5)		5 (38.5)		4 (30.8)		3 (23.1)		5 (38.5)
Peritoneal seeding
Absence	40	14 (35.0)	NS	25 (62.5)	0.019	23 (57.5)	0.034	14 (35.0)	NS	19 (47.5)	NS	25 (62.5)	NS
Presence	10	3 (30.0)		2 (20.0)		2 (20.0)		3 (30.0)		2 (20.0)		3 (30.0)
TNM stage
I	14	0 (0.0)	0.008	4 (28.6)	0.005	2 (14.3)	0.001	5 (35.7)	NS	6 (42.9)	NS	6 (42.9)	NS
II	13	8 (61.5)		12 (92.3)		11 (84.6)		3 (23.1)		7 (53.8)		9 (69.2)
III	10	4 (40.0)		6 (60.0)		7 (70.0)		5 (50.0)		5 (50.0)		8 (80.0)
IV	13	5 (38.5)		5 (38.5)		5 (38.5)		4 (30.8)		3 (23.1)		5 (38.5)
MMR status
Proficient	43	12 (27.9)	0.037	20 (46.5)	0.009	18 (41.9)	0.005	15 (34.9)	NS	16 (37.2)	NS	22 (51.2)	NS
Deficient	7	5 (71.4)		7 (100.0)		7 (100.0)		2 (28.6)		5 (71.4)		6 (85.7)

PD-L1: Programmed cell death-ligand 1; PD-L2: Programmed cell death-ligand 2; CPS: Combined positive score; WD: Well differentiated; MD: Moderately differentiated; PD: Poorly differentiated; Muc: Mucinous adenocarcinoma; NS: Not significant.

Table 3 Clinicopathological correlation of CD8, FoxP3, and FoxP3/CD8

	No.	FoxP3		CD8		FoxP3/CD8
	No.	N (%)	P value	N (%)	P value	N (%)	P value
Age
≤ 68	27	14 (51.9)	NS	14 (51.9)	NS	14 (51.9)	NS
> 68	23	11 (47.8)		11 (47.8)		11 (47.8)
Sex
Female	15	7 (46.7)	NS	8 (53.3)	NS	8 (53.3)	NS
Male	35	18 (51.4)		17 (48.6)		17 (48.6)
Site
Duodenum and jejunum	45	22 (48.9)	NS	23 (51.1)	NS	22 (48.9)	NS
Ileum	5	3 (60.0)		2 (40.0)		3 (60.0)
Histology
WD, MD	41	21 (51.2)	NS	21 (51.2)	NS	20 (48.8)	NS
PD, Muc	9	4 (44.4)		4 (44.4)		5 (55.6)
Depth
pT1-2	14	4 (28.6)	0.059	7 (50.0)	NS	4 (28.6)	0.059
pT3-4	36	21 (58.3)		18 (50.0)		21 (58.3)
Lymph node metastasis
Absence	27	11 (40.7)	NS	17 (63.0)	0.047	8 (29.6)	0.002
Presence	23	14 (60.9)		8 (34.8)		17 (73.9)
Distant metastasis
Absence	37	16 (43.2)	NS	22 (59.5)	0.024	14 (37.8)	0.004
Presence	13	9 (69.2)		3 (23.1)		11 (84.6)
Peritoneal seeding
Absence	40	19 (47.5)	NS	23 (57.5)	0.034	16 (40.0)	0.005
Presence	10	6 (60.0)		2 (20.0)		9 (90.0)
TNM stage
I	14	4 (28.6)	NS	7 (50.0)	NS	4 (28.6)	0.011
II	13	7 (53.8)		10 (76.9)		4 (30.8)
III	10	5 (50.0)		5 (50.0)		6 (60.0)
IV	13	9 (69.2)		3 (23.1)		11 (84.6)
MMR status
Proficient	43	19 (44.2)	0.049	20 (46.5)	NS	22 (51.2)	NS
Deficient	7	6 (85.7)		5 (71.4)		3 (42.9)

WD: Well differentiated; MD: Moderately differentiated; PD: Poorly differentiated; Muc: Mucinous adenocarcinoma; NS: Not significant.

Table 4 Mutual relationship of programmed cell death-ligand 1, programmed cell death-ligand 2, CD8 and FoxP3 (n = 50)

	I-PD-L1	PD-L1 CPS ≥ 10	T-PD-L2	I-PD-L2	PD-L2 CPS ≥ 10	FoxP3	CD8	FoxP3/CD8
T-PD-L1	0.002	< 0.001	0.042	0.003	0.001	NS	0.007	NS
I-PD-L1		< 0.001	NS	0.019	0.002	0.005	0.047	NS
PD-L1 CPS ≥ 10			NS	0.010	0.004	0.048	0.011	NS
T-PD-L2				< 0.001	< 0.001	NS	NS	NS
I-PD-L2					< 0.001	NS	0.002	0.045¹
PD-L2 CPS ≥ 10						NS	0.004	NS
FoxP3							NS	0.002
CD8								< 0.001¹

¹An inverse relationship.

PD-L1: Programmed cell death-ligand 1; PD-L2: Programmed cell death-ligand 2; NS: Not significant.

Table 5 Univariate and multivariate Cox proportional hazards analysis for cancer-specific survival (n = 50)

Variables	Categories	Univariate analysis		Multivariate analysis
Variables	Categories	HR (95%CI)	P value	HR (95%CI)	P value
Histological type	PD, Muc vs. WD, MD	2.252 (0.799-6.348)	NS
Depth	pT3-4 vs. pT1-2	39.308 (0.661-2337.048)	NS
Lymph node metastasis	Positive vs. negative	42.764 (5.639-324.314)	< 0.001	66.320 (7.494-586.923)	< 0.001
T-PD-L1	Positive vs. negative	0.733 (0.261-2.059)	NS
I-PD-L1	Positive vs. negative	0.367 (0.137-0.980)	0.046	1.156 (0.231-5.769)	NS
PD-L1 CPS ≥ 10	Positive vs. negative	0.621 (0.240-1.606)	NS
T-PD-L2	Positive vs. negative	0.702 (0.249-1.981)	NS
I-PD-L2	Positive vs. negative	0.243 (0.070-0.840)	0.025	0.113 (0.020-0.650)	0.015
PD-L2 CPS ≥ 10	Positive vs. negative	0.493 (0.191-1.276)	NS
FoxP3	High vs. low	1.067 (0.423-2.694)	NS
CD8	High vs. low	0.311 (0.111-0.872)	0.026	1.922 (0.164-22.481)	NS
FoxP3/CD8	High vs. low	4.490 (1.476-13.660)	0.008	1.476 (0.138-15.769)	NS

HR: Hazard ratio; 95%CI: 95% confidence interval; PD-L1: Programmed cell death-ligand 1; PD-L2: Programmed cell death-ligand 2; NS: Not significant.

Citation: Hoshimoto A, Tatsuguchi A, Hamakubo R, Nishimoto T, Omori J, Akimoto N, Tanaka S, Fujimori S, Hatori T, Shimizu A, Iwakiri K. Clinical significance of programmed cell death-ligand expression in small bowel adenocarcinoma is determined by the tumor microenvironment. World J Gastroenterol 2023; 29(40): 5566-5581
URL: https://www.wjgnet.com/1007-9327/full/v29/i40/5566.htm
DOI: https://dx.doi.org/10.3748/wjg.v29.i40.5566