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

C Chen, M Xue, W Zhang, J Xie, CM Coopersmith… - JCI insight, 2019 - ncbi.nlm.nih.gov
C Chen, M Xue, W Zhang, J Xie, CM Coopersmith, ML Ford
JCI insight, 2019ncbi.nlm.nih.gov
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 …
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.
ncbi.nlm.nih.gov