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2B4 but not PD-1 blockade improves mortality in septic animals with preexisting malignancy
Ching-wen Chen, … , Craig M. Coopersmith, Mandy L. Ford
Ching-wen Chen, … , Craig M. Coopersmith, Mandy L. Ford
Published November 14, 2019
Citation Information: JCI Insight. 2019;4(22):e127867. https://doi.org/10.1172/jci.insight.127867.
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Categories: Research Article Immunology

2B4 but not PD-1 blockade improves mortality in septic animals with preexisting malignancy

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Abstract

In addition to its well-known beneficial effects for the treatment of several types of cancer, PD-1 blockade has shown encouraging results in preclinical models of sepsis and in a recent clinical trial in sepsis. Because cancer is the most common comorbidity in septic patients, here we aimed to determine the efficacy of PD-1 checkpoint blockade in the setting of sepsis complicated with preexisting malignancy. In a model of established lung cancer followed by cecal ligation and puncture–induced (CLP-induced) sepsis, PD-1 blockade exhibited no therapeutic effect on sepsis survival. This diminished efficacy of PD-1 blockade in cancer septic animals (septic animals with cancer) was characterized by a reduction in both the quality and quantity of PD-1+ responder cells. Specifically, CD8+ T cells isolated from cancer septic animals exhibited decreased CD28 expression and a reduction in the CXCR5+PD-1+ subset. In addition, flow cytometric analysis of T cells isolated from cancer septic animals revealed 2B4 as another possible checkpoint under these conditions. Administration of anti-2B4 to cancer septic animals significantly improved sepsis survival and was associated with increased T cell costimulatory receptor expression and decreased coinhibitory receptor expression. These results illustrate functions of coinhibitory receptors in the setting of sepsis complicated with cancer.

Authors

Ching-wen Chen, Ming Xue, Wenxiao Zhang, Jianfeng Xie, Craig M. Coopersmith, Mandy L. Ford

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Figure 4

SPADE algorithm identifies 2 CD8+ T cell clusters that are upregulated in cancer septic animals.

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SPADE algorithm identifies 2 CD8+ T cell clusters that are upregulated i...
Previously healthy (PH) animals and animals with cancer (CA) were subjected to cecal ligation and puncture (CLP) and euthanized at 24 hours after CLP. Splenocytes were stained with CD3, CD8, CD44, PD-1, 2B4, BTLA, and LAG-3. CD3+CD8+ T cells were pregated in FlowJo and exported to Cytobank. SPADE analysis was performed using the 50 node setting. PH animals are defined as a baseline to benefit group comparisons. (A) Representative SPADE tree figure generated by the algorithm. Tree figure (top row left) represents PH septic animals, and tree figure (top row right) represents cancer septic animals. The clusters were discovered by multiple t tests with adjustment. Only the clusters upregulated in animals with cancer are shown here. (B) Summary plot of percentage of 2 clusters among total CD8+ T cells. (C) Phenotype histograms of 2 clusters. The gray line represents total CD8+ T cells from PH CLP mice, serving as a baseline. n = 10–11. The multiple t test was performed to identify significantly changed nodes. ***P < 0.0001
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