Single-cell transcriptomics reveal hyperacute cytokine and immune checkpoint axis in patients with poor neurological outcomes after cardiac arrest

Neurological injury is a major driver of mortality among patients hospitalized after cardiac arrest (CA). The early systemic inflammatory response after CA is associated with neurological injury and mortality but remains poorly defined. We determine the innate immune network induced by clinical CA at single-cell resolution. Immune cell states diverge as early as 6h post-CA between patients with good or poor neurological outcomes at hospital discharge. Nectin-2+ monocyte and Tim-3+ natural killer (NK) cell subpopulations associate with poor outcomes, and interactome analysis highlights their crosstalk via cytokines and immune checkpoints. Ex vivo studies on peripheral blood cells from CA patients demonstrate that immune checkpoints are a compensatory mechanism against inflammation after CA. IFNγ/IL-10 induce Nectin-2 on monocytes; in a negative feedback loop, Nectin-2 suppresses IFNγ production by NK cells. The initial hours after CA may represent a window for therapeutic intervention in the resolution of inflammation via immune checkpoints. ### Competing Interest Statement E.Y.K. is a member of the advisory board for Cell Reports Medicine. In disclosures unrelated to this work, RMB serves on Advisory Boards for Merck and Genentech. E.Y.K. is a member of the Steering Committees for and receives no financial remuneration from [NCT04409834][1] (Prevention of arteriovenous thrombotic events in critically ill COVID-19 patients, TIMI group) and REMAP-CAP ACE2 renin-angiotensin system (RAS) modulation domain. E.Y.K. receives unrelated research funding from Bayer AG, Roche Pharma Research and Early Development, the U.S. National Institutes of Health, the American Lung Association, and the Bell Family Fund. In the past E.Y.K. received unrelated research funding from Windtree Therapeutics and USAID. D.A.M. and E.A.B. are members of the TIMI Study Group which has received institutional research grant support through Brigham and Womens Hospital from: Abbott Laboratories, Amgen, Anthos Therapeutics, Arca Biopharma, AstraZeneca, Bayer HealthCare Pharmaceuticals, Inc., Daiichi-Sankyo, Eisai, Intarcia, Janssen, Merck, Novartis, Pfizer, Quark Pharmaceuticals, Regeneron, Roche, Siemens, and Zora Biosciences. DAM has received consulting fees from Arca Biopharma, Bayer, InCarda, Inflammatix, Merck, Novartis, and Roche Diagnostics. The remaining authors have no other disclosures or conflicts of interest relevant to this work. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT04409834&atom=%2Fbiorxiv%2Fearly%2F2022%2F04%2F05%2F2022.04.04.487033.atom