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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 6

Traditional FlowJo gating strategy confirms the findings from SPADE and CITRUS.

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Traditional FlowJo gating strategy confirms the findings from SPADE and ...
Using traditional FlowJo gating strategy, PD-1 and 2B4 coexpressing or single expressing cells were analyzed among CD8+ T cells. (A) Representative flow plots for PD-1 and 2B4 expression in previously healthy (PH) cecal ligation and puncture (CLP) and cancer (CA) CLP animals. (B) Summary plots of different populations among total CD8+ cells. n = 10–11. The 2-tailed Student’s t test was performed. **P < 0.01, ***P < 0.001.
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