. 2019 Dec 24;10(67):7142–7155. doi: 10.18632/oncotarget.27392

Table 1. Characteristics of included studies.

Study, Year	Biomarker	Location	Outcome	HR	Covariates in adjustment model	n of Patients	Male (%)	Stage (%)	Histology (%)	Smoking Status	Cutoff Value
Takanami, 2000 [25]	MCs	Tumor	OS	Adj	gender, T, N, differentiation, microvascular density	180	56	I: 55	ADC: 100	NR	MCD>21
								II: 14
								III: 31
Pelletier, 2001 [26]	CD20	Peritumor	OS	Adj	stage, histology, gender	113	60	I: 58	ADC: 50	Current: 92%	>10%
								II: 18	SCC: 42
								III: 24	LCC: 3
									Other: 5
Kojima, 2002 [27]	CD68 MCs	Intratumor	OS	Unadj and Adj	VEGF, microvessel density	132	67	I: 100	ADC: 71	NR	Mean
Kojima, 2002 [27]	CD68 MCs	Intratumor	OS	Unadj and Adj	VEGF, microvessel density	132	67	I: 100	SCC: 29	NR	Mean
Villegas, 2002 [28]	CD57	Intratumor	OS	Unadj and Adj	stage, age, endoscopy localization	50	98	I: 82	SCC: 100	Current: 74%	Median
								II: 12		Former: 22%
								III: 6		Never: 4%
Pelosi, 2004 [29]	MCs	Tumor	OS & DFS	Unadj and Adj	age, diameter, pT, Ki-67 labelling index, HER-2, tumor grade, symptoms, blc-2, synaptophysin	201	91	I: 100	ADC: 44	NR	≥5%
Pelosi, 2004 [29]	MCs	Tumor	OS & DFS	Unadj and Adj		201	91	I: 100	SCC: 56	NR	≥5%
Kojima, 2005 [30]	CD68 MCs	Tumor		Unadj and Adj (adenocarcinoma only)	tumor VEGF, tumor VEGF-C, tumor VEGFR-3, microvessel density	129	48	I: 100	ADC: 100	Smoker: 40%	Staining score >3
Kojima, 2005 [30]	CD68 MCs	Tumor		Unadj and Adj (adenocarcinoma only)		129	48	I: 100	ADC: 100	Non-smoker: 60%	Staining score >3
Petersen, 2006 [31]	CD3	Tumor	DFS	Unadj	n/a	64	53	I: 100	ADC: 46	Mean pack-year 51 ± 33	Score ≥2 (median)
									SCC: 34
									Other: 19
Kikuchi, 2007 [32]	CD8	Cancer-Nest	OS	Unadj	n/a	161	68	I: 59^*	ADC: 52	Never: 24%	1-cell increment
	CD56							II/III/IV: 41	SCC: 42	Ever: 67%
									Other: 6	Unknown: 9%
Dieu-Nosjean, 2008 [33]	CD3	Tumor	OS & DFS	Unadj	n/a	74	81	I: 84	ADC: 62	Current: 91%	1.5 mean score
Dieu-Nosjean, 2008 [33]	CD20	Tumor	OS & DFS	Unadj	n/a	74	81	II: 16	SCC: 38	Never: 9%	1.5 mean score
Shimizu, 2010 [34]	FoxP3	Intratumor	DFS	Adj	nodal involvement, COX-2 expression	100	60	I: 68	ADC: 69	NR	≥3%
								II: 14	SCC: 31
								III: 18
da Costa Souza, 2012 [35]	CD4		OS	Adj	stage and histological type	65	69	I: 31	ADC: 58	Pack-years median 41(0–120)	CD4: ≥16.1%
	CD8							II: 51	SCC: 31		CD8: ≥1.8%
	CD68							III: 18	LCC: 11		CD68: ≥4.5%
Hanagiri, 2013 [36]	FoxP3	Regional Lymph Nodes	OS	Unadj and Adj	gender, pack-year index, T factor, N factor	158	65	I: 72	ADC: 59	NR	>0.5% PBL
								II: 11	SCC: 22		>1.1% RLNL
								III: 19	Other: 9
Suzuki, 2013 [37]	FoxP3	Stroma	DFS	Unadj and Adj	gender, stage, lymphatic invasion, IL-12R, IL-7R	956 (478)	36	I: 100	ADC: 100	Current: 16%	Score ≥2
										Former: 69%
										Never: 15%
Feng, 2014 [38]	CD68	Islet and Stroma	OS & DFS	Adj	mediastinal down staging, islet/stromal machrophage ratio	28	54	III: 100	ADC: 70	Smoker: 39%	median
Feng, 2014 [38]	CD68	Islet and Stroma	OS & DFS	Adj	mediastinal down staging, islet/stromal machrophage ratio	28	54	III: 100	SCC: 21	Never: 61%	median
Germain, 2014 [39]	CD20	Tumor	OS	Unadj	n/a	74	81	I: 84	ADC: 62	Current: 91%	CD20: 0.0255 mm²/tumor IPF
Germain, 2014 [39]	CD20	Tumor	OS	Unadj	n/a	74	81	II: 16	SCC: 38	Never: 9%	CD20: 0.0255 mm²/tumor IPF
Hanagiri, 2014 [40]	FoxP3	Regional Lymph Nodes	OS	Unadj and Adj	gender, age, histology	131	57	I: 100	ADC: 76	NR	Relative expression > 0.06
									SCC: 16
									Other: 8
Lee, 2014 [41]	CD68		DFS	Adj	procedure, stage, CD68, FoxP3/CD3	151	40	I: 100	ADC: 77	Current: 7%	Score ≥2
									SCC: 23	Former: 72%
										Never: 21%
Djenidi, 2015 [42]	CD3	Total (tumor + stroma)	OS & DFS	Unadj	n/a	101	68	I: 100	ADC: 45	Ever: 89%	Continuous variables
	CD8								SCC: 42
									Other: 13
Hernandez-Prieto, 2015 [43]	CD3	Stroma	DFS	Unadj	n/a	84	86	I: 71	ADC: 48	Current: 43%	Moderate 10%
	CD4							II: 29	SCC: 46	Former: 51%	Strong 20%
	CD8								LCC: 2	Never: 6%
	CD20								Other: 4
	CD57
Kadota, 2015 [44]	CD3	Tumor	OS	Unadj	n/a	331	60	I: 57	SCC: 100	≤90 pack-year: 81%	CD3: High ≥50
	CD4							II: 28		>90 pack-year: 19%	CD4: High ≥20
	CD8							III: 15			CD8: High ≥50
	CD20										CD20: High ≥20
	CD68										CD68: High ≥50
	FoxP3										FoxP3: High ≥20
	Neutrophil-(CD10)										CD10: High ≥10
Kim, 2015 [45]	CD8	Tumor	OS & DFS	Unadj	n/a	331	96	I: 40	SCC: 100	Smoker: 91%	Median
								II: 36		Never: 5%
								III: 24
Donnem, 2015 [46]	CD8	Stroma	OS & DFS	Adj	stage, differentiation, histology, age	797	64	I: 51	ADC: 48	NR	High density >50%
								II: 35	SCC: 45
								III: 15	LCC: 7
Li, 2015 [47]	CD68		OS & DFS	Adj	TNM, N stage, subcarinal lymph node, n number of nodal stations involved, number of involved nodes	159	69	I: 23	ADC: 26	Smoker: 31%
								II: 36	SCC: 52	Never: 69%
								III: 24
O’Callaghan, 2015 [48]	CD3	TI/S	OS	Unadj and Adj	tumor size, stage, lymph node stage, WHO overall stage, positive resection margins, TI/S biomarker ratios	197 (186)	62	I: 55	ADC: 45	Current & Former: 94%	Median
	CD8							II: 24	SCC: 46	Never: 6%
	FoxP3							III: 21	LCC: 3
	FoxP3								Other: 6
Paulsen, 2015 [49]	CD8	Tumor	OS	Unadj	n/a	536	68	I: 48	ADC: 38	Current: 33%	score of ≥2
								II: 36	SCC: 54	Former: 64%
								III: 16		Never: 3%
Tian, 2015 [50]	CD3	Tumor	OS	Adj	histology, pT, pN, pTNM stage, CD3, CD8, IL-2	129	71	I: 37	ADC: 37	Smoker: 37%	H-score 0–4 = low expression
	CD8							II: 22	SCC: 47	Never: 63%	H-score 5–12 = high expression
								III: 40	Other: 16
Ameratunga, 2016 [51]	CD8	Stroma	OS & DFS	Unadj and Adj	age, sex, pneumonectomy status, nodal stage, histology, smoking status, CD8+, FOXP3, PD-L1	527 (509)	69	NR	ADC: 55	Heavy: 73%	Score of % of positively stained cells > 3
									SCC: 34	Light: 17%
									Other: 11	Never: 7%
										Unknown: 4%
Kinoshita, 2016 [52]	CD4	Tumor	OS & DFS	Unadj and Adj (for CD20 only)	age, diameter, nodal metastasis, pleural invasion, FoxP3/CD4	218	65	I: 71	ADC: 72	Ever: 61%	CD4: > 251 cells/mm²
	CD8							II: 11	SCC: 18	Never: 39%	CD8: > 110 cells/mm²
	CD20							III: 18	Other: 10		FoxP3: > 163 cells/mm²
	FoxP3
Parra, 2016 [53]	CD57	Peri and intra tumor	OS (CD57 only) & DFS	Adj	tumor stage, adjuvant therapy	254	55	I: 50	ADC: 57	Current: 45%	Median
	CD68							II: 30	SCC: 43	Former: 30%
								III: 20		Never: 17%
Teng, 2016 [54]	CD8	Tumor	OS & DFS	Unadj and Adj (for CD8 only)	high risk, FoxP3/CD8+TILS	126	67	I: 100	ADC: 45	NR	CD3: ≥30%
	FoxP3								SCC: 33		FoxP3: ≥45/HPF
									LCC: 22
Uso, 2016 [55]	CD8	Tumor and Stroma	OS & DFS (CD8 only)	Adj	Tumoral CD8+ cells, Stromal FOXP3+ cells, FOXP3+ stroma/CD4+ tumor, FOXP3+ stroma/CD8+ tumor	122	85	I: 59	ADC: 42	Current: 48%	CD8: Median
	FoxP3							II: 21	SCC: 47	Former: 38%	FoxP3: >10%
								III: 20	Other: 11	Never: 14%
Yang, 2016 [56]	CD4	Tumor and Stroma	OS & DFS	Adj	age, sex, stage, PD-L1 expression, Stromal CD4+ T cell, Stromal regulatory T cell, Epithelial CD8+ T cell	105	85	I: 100	SCC: 100	Smoker: 75%	CD4: ≥5% (tumor) & ≥25% (stroma)
	CD8									Non Smoker: 25%	CD8: ≥5% (tumor) & ≥50% (stroma)
	FoxP3										FoxP3: ≥20%
Yazdi, 2016 [57]	CD8	Stroma	OS	Unadj and Adj	stage, sex, HLA-E	197	50	I: 31	ADC: 100	NR	mean
								II: 38
								III: 18
Huang, 2017 [58]	CD8	Tumor	OS & DFS	Adj	age, sex, differentiation, histology, tumor, node, CD133, OCT-4, CD8, CD56, HLA I, PD-L1	172	65	NR	SCC: 42	Smoker: 55%	Median
Huang, 2017 [58]	CD56	Tumor	OS & DFS	Adj		172	65	NR	Other: 58	Non-Smoker: 45%	Median
Kinoshita, 2017 [59]	CD4	Tumor	OS & DFS	Unadj	n/a	164	5	I: 68	ADC: 100	Non-smoker: 100%	CD4: > 585 cells/mm²
	CD8							II, III: 32			CD8: > 900 cells/mm²
	CD20										CD20: > 1070 cells/mm²
	FoxP3										FoxP3: > 81 cells/mm²
Koh, 2017 [60]	CD8 [60]	Tumor	DFS	Adj	age, lymph node metastasis, CD103+ TILs, CD8+ TILs	378	95	I, II: 79	SCC: 100	Smoker: 90%	mean
Koh, 2017 [60]	CD8 [60]	Tumor	DFS	Adj	age, lymph node metastasis, CD103+ TILs, CD8+ TILs	378	95	III: 21	SCC: 100	Never: 5%	mean
Sepesi, 2017 [61]	CD3	Intratumor	OS	Unadj and Adj	age, histology, thoracotomy, adjuvant therapy, DLCO %, Zubrod score, Lobectomy, PD-L1 tumor H score, PD-L1 tumor % expression, PD-L1 macrophages H score, PD-L1 macrophages % expression, CD3, CD4, CD8, CD45RO, CD57, CD68, FoxP3, PD-1	113	49	I: 100	ADC: 70	Current and Former: 89%	CD3: ≥ 827.3
	CD4								SCC: 30	Never: 11%	CD4 ≥ 852.1
	CD8										CD8: ≥ 292.3
	CD57										CD57: ≥ 1408
	CD68										CD68: ≥ 515
	FoxP3										FoxP3: ≥ 460.3
Ye, 2017 [62]	CD8		OS	Unadj and Adj	gender, age, pathology grade, T, N, clinical stage	102	54	I: 20	ADC: 100	NR	final score>6
								II: 59
								III: 21
Barua, 2018 [63]	CD4	Tumor	OS	Unadj	n/a	120	43	I: 4	ADC: 60	Current & Former: 83%	G-cross signatures
	CD8							II: 11	SCC: 29	Never: 17%
	CD68							III: 85	Other: 11
	FoxP3
Jackute, 2018 [64]	CD68	Total	OS	Unadj	n/a	80	80	I: 29	ADC: 48	Smoker: 83%	Median
								II: 33	SCC: 45	Non-Smoker: 17%
								III: 39	Other: 7
Mazzaschi, 2018 [65]	CD3		OS & DFS	Unadj	n/a	100	4	I: 35	ADC: 42	Current: 37%	Continuous
	CD8							II: 41	SCC: 58	Former: 52%
								III: 24		Never: 9%
Su, 2018 [66]	CD8	Stroma	OS & DFS	Adj	age, sex, smoking, micropapillary pattern, CEA, PD-1 expression	223	54	I: 67	ADC: 100	Smoker: 30%	≥25%
								II: 14		Non-Smoker: 70%
								III: 19
Matsubara, 2019 [67]	CD3	Tumor Margins	OS	Unadj and Adj	age, stage, lymphatic invasion, PD-L1, PD-L2	211	83	I: 54	SCC: 100	Smokers ≥30 pack-years: 85%	Median
	CD4							II: 35
	CD8							III: 11
Meng, 2019 [68]	CD4^{^}	Tumor (FoxP3 Stroma)	OS	Adj	T, N, CD4, CD8, FoxP3, PD-L1	197	65	I: 57	SCC: 43	Smoker: 58%	CD4: 5%
	CD8^*							II: 45	Non-SCC: 57	Non-smoker: 42%	CD8: 5%
	FoxP3^*							III: 40			FoxP3: 20%
Cao, 2019 [69]	CD68	Tumor	OS & DFS	Unadj and Adj	T, N	137	56	I: 34	ADC: 68	Former or Current: 48%	Median
								II: 34	SCC: 32	Never: 53%
								III: 33

^*HR reported for stage I only. ^{^}HR reported for squamous only.

^#ADC = adenocarcinoma, SCC = squamous cell carcinoma, LCC = large cell carcinoma, NR = not reported, n/a = not applicable, OS = overall survival, DFS = disease free survival, Adj = adjusted for covariates, Unadj = not adjusted for covariates.