Prognostic value of Cox-2 and PD-L1 expression and its relationship with tumor-infiltrating lymphocytes in resected lung adenocarcinoma

Figures & data

Figure 1 Representative sections of lung adenocarcinoma tissues with cytoplasmic staining for Cox-2. (A) High expression; (B) low expression.

Abbreviation: Cox-2, cyclooxygenase-2.

Figure 2 Representative sections of lung adenocarcinoma tissues with CD8-positive TILs and cell membrane staining for PD-L1 according to tumor immune microenvironment classification.

Abbreviations: CD8-positive TILs, tumor-infiltrating CD8-positive T lymphocytes; PD-L1, programmed cell death-1 ligand 1.

Table 1 Relationship between CD8-positive TILs count and biomarkers

Variable		CD8-positive TILs count	P-value
PD-L1			0.010
Negative	111	69.66±47.91
Positive	59	93.75±60.95
Cox-2			0.020
Low	92	86.78±54.74
High	78	67.68±51.25
EGFR mutation			0.040
Negative	50	83.80±49.25
Positive	43	62.84±47.41
Smoking status			0.124
Never	90	71.97±49.83
Smoker	80	84.83±57.63
Lymphocyte count			0.575
<1900	86	75.72±54.75
>1900	84	80.37±53.17

Abbreviations: CD8-positive TILs, tumor-infiltrating CD8-positive T lymphocytes; Cox-2, cyclooxygenase-2; PD-L1, programmed cell death-1 ligand 1.

Figure 3 The numbers of CD8-positive TILs within cancer cell nest were significantly lower in cases with low PD-L1 expression (A; P=0.010) and high-Cox-2 expression (B; P=0.020). Differences were tested using the Mann–Whitney U-test.

Abbreviations: CD8-positive TILs, tumor-infiltrating CD8-positive T lymphocytes; Cox-2, cyclooxygenase-2; PD-L1, programmed cell death-1 ligand 1.

Table 2 Relationship of PD-L1 and Cox-2 expression and clinicopathological factors

Variable	PD-L1 expression			Cox-2 expression
	Negative	Positive	P-value	Low	High	P-value
Number	111	59		92	78
Age			0.913			0.878
≥70	48	25		40	33
<70	63	34		52	45
Sex			<0.001			0.006
Male	39	42		35	46
Female	72	17		57	32
Smoking history			<0.001			0.007
Smoker	36	41		33	44
Never smoker	75	18		59	34
Clinical T category (TNM-7)			0.631			0.174
T1	81	41		70	52
T2	30	18		22	26
Histological subtype			0.001			0.026
Lepidic	47	11		38	20
Acinar	34	19		28	25
Papillary	26	19		23	22
Solid	4	10		3	11
Pathological nodal status			0.108			0.036
N0	94	44		80	58
N1+2	17	15		12	20
Pathological stage (TNM-7)			0.267			0.121
IA	54	20		48	26
IB	36	20		28	28
IIA+IIB	9	8		6	11
IIIA	12	11		10	13
EGFR mutation status			0.001			0.856
Positive	35	8		21	22
Negative	23	26		23	26
Unknown	53	25		48	30

Abbreviations: Cox-2, cyclooxygenase-2; PD-L1, programmed cell death-1 ligand 1; TNM, tumor, node, and metastasis.

Table 3 Relationship of tumor immune microenvironment and clinicopathological factors

Variable	Type I	Type II	Type III	Type IV	P-value
Number	30	71	29	40
Age					0.645
≥70	11	33	14	15
<70	19	38	15	25
Sex					0.001
Male	23	21	19	18
Female	7	50	10	22
Smoking history					<0.001
Smoker	24	21	19	16
Never	6	50	10	24
Clinical T category (TNM-7)					0.924
T1	22	54	19	27
T2	8	17	10	13
Histological subtype					0.027
Lepidic	6	33	5	14
Acinar	9	19	10	15
Papillary	9	16	10	10
Solid	6	3	4	1
Pathological Nodal status					0.253
N0	24	59	20	35
N1+2	6	12	9	5
Pathological stage (TNM-7)					0.016
IA	12	37	8	17
IB	11	20	9	16
IIA+IIB	4	4	4	5
IIIA	3	10	8	2
EGFR mutation status					0.001
Positive	4	27	4	8
Negative	13	9	13	14
Unknown	13	35	12	18

Note: Type I (PD-L1 positive with TILs driving), type II (PD-L1 negative with no TIL), type III (PD-L1 positive with no TIL), and type IV (PD-L1 negative with TILs driving).

Abbreviations: PD-L1, programmed cell death-1 ligand 1; TILs, tumor-infiltrating T lymphocytes; TNM, tumor, node, and metastasis.

Figure 4 Comparison of recurrence-free survival rates between patients with high CD8-positive TILs counts versus those with low CD8-positive TILs counts (A), high PD-L1 expressions versus low PD-L1 expressions (B), and tumor microenvironment type IV versus type I versus type II versus type III (C). P=0.038, 0.006, and 0.002, respectively.

Abbreviations: CD8-positive TILs, tumor-infiltrating CD8-positive T lymphocytes; PD-L1, programmed cell death-1 ligand 1.

Figure 5 Comparisons of recurrence-free survival rates between patients with high Cox-2 expression versus low Cox-2 expression, according to tumor microenvironment status: type I (A), type II (B), type III (C), and type IV (D). P=0.616, 0.021, 0.842, and 0.208, respectively.

Abbreviations: CD8-positive TILs, tumor-infiltrating CD8-positive T lymphocytes; Cox-2, cyclooxygenase-2; PD-L1, programmed cell death-1 ligand 1.

Table 4 Results of the univariate and multivariate cox regression analyses of recurrence-free survival

Variable	Univariate			Multivariate
	HR	95% CI	P-value	HR	95% CI	P-value
Sex
Male/female	1.51	0.83–2.75 0.176
Age
≥70/<70	1.28	0.71–2.32	0.411
Histological subtype
Nonlepidic/lepidic	6.49	2.32–18.17	<0.001	4.33	1.51–12.5	0.007
Pathological T (TNM-7)
T2/T1	1.72	0.93–3.16	0.084
Pathological N factor
Positive/negative	8.58	4.67–15.78	<0.001	6.36	3.37–11.99	<0.001
Cox-2 expression
High/low	2.05	1.11–3.76	0.021	1.10	0.58–2.10	0.773
PD-L1 expression
Positive/negative	2.30	1.27–4.16	0.006	1.96	1.04–3.69	0.037
CD8-positive TILs count
High/low	0.50	0.26–0.96	0.038	0.41	0.21–0.82	0.012

Abbreviations: Cox-2, cyclooxygenase-2; PD-L1, programmed cell death-1 ligand 1; TILs, tumor-infiltrating T lymphocytes; TNM, tumor, node, and metastasis.