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

• Type of Material: Article
• Authors: Ching-wen Chen, Emory University; Ming Xue, Emory University; Wenxiao Zhang, Emory University; Jianfeng Xie, Emory University; Craig Coopersmith, Emory University; Mandy Ford, Emory University
• Language: English
• Date: 2019-11-14
• Publisher: American Society for Clinical Investigation
• Publication Version: Final Published Version
• Copyright Statement: © 2019, American Society for Clinical Investigation.
• Final Published Version (URL): http://dx.doi.org/10.1172/jci.insight.127867
• Title of Journal or Parent Work: JCI Insight
• Volume: 4
• Issue: 22
• Grant/Funding Information: This work was funded by R01s GM104323 and GM113228 to MLF and CMC.
• Keywords: EXPRESSION; IMMUNOSUPPRESSION; DYSFUNCTION; ANTIBODY; CANCER-PATIENTS; PREVENTION; SEVERE SEPSIS; Life Sciences & Biomedicine; CD8(+) T-CELLS; SURVIVAL; Medicine, Research & Experimental; EPIDEMIOLOGY; Science & Technology; Research & Experimental Medicine
• Research Categories: Health Sciences, Medicine and Surgery; Health Sciences, Epidemiology

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.