Prognostic significance of Lymphocyte-activation gene 3 (LAG3) in patients with solid tumors: a systematic review, meta-analysis and pan-cancer analysis

Li, Rongyang; Qiu, Jianhao; Zhang, Zhan; Qu, Chenghao; Tang, Zhanpeng; Yu, Wenhao; Tian, Yu; Tian, Hui

doi:10.1186/s12935-023-03157-5

Table 1 Baseline characteristics of included studies regarding LAG3

From: Prognostic significance of Lymphocyte-activation gene 3 (LAG3) in patients with solid tumors: a systematic review, meta-analysis and pan-cancer analysis

Author (year)	Country	Sample size	Study type	Cancer type	Treatment	LAG3 + expression	Expression location	Cut-off value of LAG3	Method to evaluate LAG3 expression	Outcome	Method to estimate HR
Asano (2022)	Japan	177	RCS	BRCA	NAC + Surgery	47 (26.6)	TILs	NR	IHC + FISH	OS	Univariate
Asano (2022)	Japan	177	RCS	BRCA	NAC + Surgery	47 (26.6)	TILs	NR	IHC + FISH	DFS	Multivariate
Babar (2019)	USA	49	RCS	ESCA	NAC/NRT + Surgery	NR	TCs	> 2.9759	IHC	OS	Univariate
Babar (2019)	USA	49	RCS	ESCA	NAC/NRT + Surgery	NR	TCs	> 3.7521	IHC	DFS	Multivariate
Bagbudar (2022)	Turkey	238	RCS	BRCA	Surgery	179 (75.2)	TILs	> 1%	IHC	OS	Multivariate
Bagbudar (2022)	Turkey	238	RCS	BRCA	Surgery	179 (75.2)	TILs	> 1%	IHC	DFS	Univariate
Bottai (2016)	Italy	363	RCS	BRCA	AC	NR	TILs	> 5%	IHC	OS	Univariate
Bottai (2016)	Italy	363	RCS	BRCA	AC	NR	TILs	> 5%	IHC	RFS	Univariate
Chen (2021)	China	161	RCS	ESCA	Surgery	92 (57.1)	TCs	≥ 10%	IHC	OS	Univariate
Deng (2016)	China	122	RCS	HNSC	NAC/NRT + Surgery	NR	TILs	NR	IHC + IF	OS	Univariate
Duan (2018)	China	95	RCS	ESCA	Surgery	16 (16.8)	TILs	≥ 1%	IHC + IF	OS	Univariate
Fucikova (2019)	Czech	80	RCS	OV	Surgery	40 (50.0)	TCs	Median level	IHC	OS	Univariate
Fucikova (2019)	Czech	80	RCS	OV	Surgery	40 (50.0)	TCs	Median level	IHC	RFS	Univariate
Gebauer (2020)	Germany	421	RCS	ESCA	Surgery or NAC/NRT + Surgery	48 (11.4)	TILs	≥ 1%	IHC + IF	OS	Multivariate
Giraldo (2015)	France	135	RCS	KIRC	Surgery	NR	Tumor Center TILs	> 5%	IHC + IF	OS	Univariate
							Tumor Center TILs			DFS	Univariate
							Invasive Margin TILs			OS	Univariate
							Invasive Margin TILs			DFS	Univariate
Guo (2020)	China	143	RCS	LIHC	Surgery	60 (42.0)	TCs	≥ 4.9/mm2	IF	OS	Multivariate
Guo (2020)	China	143	RCS	LIHC	Surgery	60 (42.0)	TCs	≥ 4.9/mm2	IF	DFS	Multivariate
He (2017)	China	139	RCS	NSCLC	Surgery	36 (25.9)	TILs	> 20%	IHC	OS	Multivariate
He (2017)	China	139	RCS	NSCLC	Surgery	36 (25.9)	TILs	> 20%	IHC	RFS	Multivariate
Jin (2023)	China	175	RCS	BLCA	Surgery	18 (10.8)	TCs	CPS ≥ 1	IHC	RFS	Multivariate
Kim (2018)	Korea	108	RCS	OV	NAC + Surgery + AC	46 (41.8)	TILs	Median level	IHC	OS	Univariate
Kim (2018)	Korea	108	RCS	OV	NAC + Surgery + AC	46 (41.8)	TILs	Median level	IHC	PFS	Univariate
Kim (2020)	Korea	102	RCS	SKCM	Skin biopsy	44 (43.1)	TAMs	> 20%	IHC	OS	Multivariate
Kim (2020)	Korea	102	RCS	SKCM	Skin biopsy	44 (43.1)	TAMs	> 20%	IHC	PFS	Multivariate
Lee (2018)	Korea	89	RCS	COAD	Surgery	44 (49.4)	TILs	> 5%	IHC	DFS	Multivariate
Lee (2019)	Korea	124	RCS	SKCM	Skin biopsy	55 (44.4)	TILs	> 20%	IHC + IF	OS	Multivariate
Ligon (2021)	USA	25	RCS	SARC	Surgery or Surgery + AC	NR	TCs	NR	IHC + FC	PFS	Univariate
Luo, C (2021)	China	31	RCS	LIHC	Surgery	NR	TCs	> 5%	IHC	OS	Univariate
Luo, C (2021)	China	31	RCS	LIHC	Surgery	NR	TCs	> 5%	IHC	DFS	Univariate
Luo, F (2021)	China	182	RCS	HNSC	Surgery + AC/RT/AC + RT	147 (80.8)	TILs	> 14/mm2	IHC	DFS	Multivariate
Luo (2022)	China	113	RCS	THCA	Surgery + I₁₃₁/AC/RT/AC + RT	NR	TILs	CPS ≥ 1	IHC	OS	Univariate
Lv (2021)	China	564	RCS	STAD	Surgery	228 (40.4)	TILs	Median level	IHC	OS	Univariate
Lv (2021)	China	564	RCS	STAD	Surgery	228 (40.4)	TILs	Median level	IHC	DFS	Univariate
Minichsdorfer (2019)	Austria	28	RCS	HNSC	Biopsy/Surgery + AC + RT	15 (53.6)	TILs	> 5%	IHC	OS	Univariate
Minichsdorfer (2019)	Austria	28	RCS	HNSC	Biopsy/Surgery + AC + RT	15 (53.6)	TILs	> 5%	IHC	DFS	Univariate
Park (2021)	Korea	385	RCS	STAD	Surgery + AC	175 (45.5)	TCs	≥ 5%	IHC	OS	Multivariate
						25 (6.5)	TILs			OS	Univariate
						29 (7.5)	TILs			PFS	Univariate
Peng (2021)	China	76	RCS	READ	NRT + Surgery + AC	28 (36.8)	TCs	> 12.5%	IHC	DFS	Univariate
Peng (2021)	China	76	RCS	READ	NRT + Surgery + AC	26 (34.2)	TILs	> 27.5%	IHC	DFS	Multivariate
Rhyner Agocs (2021)	Switzerland	142	RCS	COAD	Surgery	98 (69.0)	TILs	> 1/mm2	IHC	DFS	Univariate
Rühle (2022)	Germany	63	RCS	HNSC	AC/RT	NR	Intraepithelial TILs	CPS ≥ 1	IHC	OS	Univariate
							Intraepithelial TILs			PFS	Univariate
							Stromal TILs			OS	Univariate
							Stromal TILs			PFS	Univariate
Sarradin (2021)	France	66	RCS	BRCA	NAC + Surgery	55 (83.3)	TCs	≥ 1%	IHC	OS	Univariate
Seifert (2021)	Germany	58	RCS	PAAD	Surgery or NAC + Surgery	29 (50.0)	TILs	Median level	IHC + IF	DFS	Multivariate
Shi (2021)	China	200	RCS	THCA	Surgery	6 (3.0)	TILs	CPS ≥ 1	IHC	RFS	Univariate
Stovgaard (2021)	Denmark	225	RCS	BRCA	Surgery + AC	37 (16.4)	intratumoral TILs	CPS ≥ 1	IHC	OS	Univariate
Stovgaard (2021)	Denmark	225	RCS	BRCA	Surgery + AC	82 (36.4)	stromal TILs	CPS ≥ 1	IHC	OS	Univariate
Stovgaard (2022)	Denmark	488	RCS	BRCA	Surgery + AC	227 (46.5)	intratumoral TILs	Median level	IHC	OS	Multivariate
						227 (46.5)	intratumoral TILs			RFS	Multivariate
						154 (31.6)	stromal TILs			OS	Multivariate
						154 (31.6)	stromal TILs			RFS	Multivariate
Tahtacı (2023)	Turkey	49	RCS	BRCA	NAC + Surgery + AC/RT	28 (57.1)	stromal TILs	> 1%	IHC	OS	Univariate
Wang, H (2019)	China	36	RCS	HNSC	TT	NR	TILs	IHC scoring > 4	IHC	OS	Multivariate
Wang, W (2019)	China	183	RCS	ESCA	Surgery	69 (37.7)	TILs	Scoring system > 3	IHC	OS	Multivariate
Wang, W (2019)	China	183	RCS	ESCA	Surgery	69 (37.7)	TILs	Scoring system > 3	IHC	RFS	Multivariate
Wang (2018)	China	114	RCS	BRCA	NAC + Surgery + AC	38 (33.3)	TILs	> 5%	IHC	DFS	Univariate
Wang (2021)	China	96	RCS	COADREAD	Surgery + AC	8 (8.3)	TCs	> 1%	IHC	OS	Univariate
Yao (2023)	China	78	RCS	ESCA	NAC + Surgery	26 (33.3)	TILs	NR	RT-PCR + WB	PFS	Multivariate
Zaitsu (2023)	Japan	171	RCS	OV	Surgery	48 (28.1)	TILs	> 20%	IHC	OS	Univariate
Zaitsu (2023)	Japan	171	RCS	OV	Surgery	48 (28.1)	TILs	> 20%	IHC	PFS	Multivariate
Zeng (2020)	China	141	RCS	BLCA	Surgery + AC	71 (50.4)	intraepithelial TILs	≥ 10 cells/HPF	IHC + FC	OS	Multivariate
						71 (50.4)	intraepithelial TILs	≥ 10 cells/HPF		PFS	Multivariate
						68 (48.2)	stromal TILs	≥ 1 cells/HPF		OS	Multivariate
						68 (48.2)	stromal TILs	≥ 1 cells/HPF		PFS	Multivariate
Zhang (2018)	China	287	RCS	ESCA	Surgery	172 (59.9)	TILs	Median level	IHC	OS	Multivariate
Zhang (2018)	China	287	RCS	ESCA	Surgery	172 (59.9)	TILs	Median level	IHC	PFS	Multivariate
Zhang (2022)	China	421	RCS	UCEC	Surgery	133 (31.6)	TCs	> 1%	IHC	RFS	Multivariate
Zhang (2022)	China	421	RCS	UCEC	Surgery	101 (24.0)	TILs	> 1%	IHC	RFS	Univariate
Zou (2023)	China	175	RCS	CESC	NAC + NRT + Surgery or Surgery + CRT/RT	50 (28.6)	TCs	CPS ≥ 1	IHC	OS	Univariate
						50 (28.6)		CPS ≥ 1		PFS	Univariate
						18 (10.3)		CPS ≥ 10		OS	Univariate
						18 (10.3)		CPS ≥ 10		PFS	Univariate

RCS, retrospective cohort study; NR, not reported; LAG3, lymphocyte- activation gene 3; HR, hazard ratio; BLCA, bladder urothelial carcinoma; BRCA, breast invasive carcinoma; CESC, cervical squamous cell carcinoma and endocervical adenocarcinoma; COAD, colon adenocarcinoma; COADREAD, colon adenocarcinoma or/and rectum adenocarcinoma; ESCA, esophageal carcinoma; HNSC, head and neck squamous cell carcinoma; KIRC, kidney renal clear cell carcinoma; LIHC, liver hepatocellular carcinoma; NSCLC, non-small cell lung carcinoma; OV, ovarian serous cystadenocarcinoma; PAAD, pancreatic adenocarcinoma; READ, rectum adenocarcinoma; SARC, sarcoma; SKCM, skin cutaneous melanoma; STAD, stomach adenocarcinoma; THCA, thyroid carcinoma; UCEC, uterine corpus endometrial carcinoma; NAC, neoadjuvant chemotherapy; NRT, neoadjuvant radiation therapy; AC, adjuvant chemotherapy; RT, radiation therapy; TT, targeted therapy; CRT: chemoradiotherapy; TCs, tumor cells; TILs, tumor-infiltrating lymphocytes; TAMs, tumor-associated macrophages; CPS, combined positive score; HPF, high-power field; IHC, immunohistochemical; IF, immunofluorescence; FC, flow cytometry; FISH, fluorescence in situ hybridization; RT-PCR, reverse transcription polymerase chain reaction; WB, Western Blotting; OS, overall survival; DFS, disease-free survival; PFS, progression-free survival; RFS, recurrence-free survival

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