Checkpoint inhibitor therapy in preclinical sepsis models: a systematic review and meta-analysis

Intensive Care Medicine Experimental

Table 1 Overview of checkpoint molecules (CPM) targeted, mouse strains studied, bacterial and additional challenges employed, and the number of total and surviving animals in control and inhibitor treatment groups in each experiment analyzed from the retrieved studies

Author, year	Exp ID	CPM target	Mouse strain	Bacterial challenge			Additional challenge	Animal numbers
Author, year	Exp ID	CPM target	Mouse strain	Organism	Site	Abx Rx	Additional challenge	Control total	Control survivors	Inhibitor total	Inhibitor survivors
Seo, 2008	1	PD-L1	C57BL6	L. monocytogenes	IV	No	None	10	10	10	3
Zhang, 2010*	1	PD-L1	C57BL6	CLP—Polymicrobial	IP	No	None	12	2	18	13
Zhang, 2010*	2	PD-L1	C57BL6	CLP—Polymicrobial	IP	No	None	12	2	18	9
Kobayashi, 2013	1	BTLA	C57BL6	LPS	IP	No	None	10	0	30	23
Cheng, 2016	1	BTLA	C57BL6	CLP—Polymicrobial	IP	No	Hemorrhage—pre	15	11	15	5
Deng, 2018^#	1	PD-L1	C57BL6	CLP—Polymicrobial	IP	No	None	20	11	20	18
Deng, 2018^#	2	PD-L1	Bmal-/-	CLP—Polymicrobial	IP	No	None	20	5	20	14
Patil, 2018	1	PD-L1	BALB/c	P. aeruginosa	ID	No	Skin Burn—pre	15	2	15	10
Patil, 2018	2	PD-L1	BALB/c	S. aureus	IV	No	Skin Burn—pre	15	2	15	8
Inoue, 2011**	1	CTLA-4	CD1	CLP—Polymicrobial	IP	Yes	None	18	1	18	6
	2	CTLA-4	CD1	CLP—Polymicrobial	IP	Yes	None	10	5	10	0
	3	CTLA-4	C57BL6	CLP—Polymicrobial	IP	Yes	None	5	0	5	2
	4	CTLA-4	CD1	CLP—Polymicrobial	IP	Yes	IV Candida—post	7	0	7	2
Chang, 2013	1	PD-1	C57BL6 or CD1	CLP—Polymicrobial	IP	Yes	IV Candida—post	74^@	25	35	20
	2	PD-L1	C57BL6 or CD1	CLP—Polymicrobial	IP	Yes	IV Candida—post	74^@	25	39	23
	3	CTLA-4	C57BL6 or CD1	CLP—Polymicrobial	IP	Yes	IV Candida—post	18	6	19	11
Shindo, 2015	1	PD-1	C57BL6	CLP—Polymicrobial	IP	Yes	IV Candida—post	30	25	28	26
Shindo, 2017	1	PD-L1	CD1	CLP—Polymicrobial	IP	Yes	IV Candida—post	33	10	32	19
Brahmamdam, 2010	1	PD-1	CD1	CLP—Polymicrobial	IP	No	None	14	4	17	12

See Table 2 for additional details regarding challenge and treatment regimens
Exp ID number assigned the experiment(s) providing survival data in each study, CPM checkpoint molecule targeted, PD-1 programmed cell death 1, PD-L1 programmed cell death ligand-1, CTLA-4 cytotoxic T lymphocyte-associated protein-4, BTLA B and T lymphocyte attenuator, Abx Rx antibiotic treatment, CLP cecal ligation and puncture, IV intravenous, IP intraperitoneal, ID intradermal, post additional challenge administered after bacterial challenge, pre additional challenge administered before bacterial challenge, LPS lipopolysaccharide
*Checkpoint inhibitor treatment administered at D−1 in experiment 1 and D0 in experiment 2
**Experiment 1 administered 50 μg and experiment 2 administered 200 μg anti-CTLA-4 in CD-1 mice, experiment 3 administered 50 μg anti-CTLA-4 in C57BL6 mice
^#Experiment 1 performed in C57BL6J mice and experiment 2 performed in Bmal1^Mye-/- mice
^@A common control group used for these two experiments