MURINE PANCREATIC CANCER ALTERS T CELL ACTIVATION AND APOPTOSIS AND WORSENS SURVIVAL AFTER CECAL LIGATION AND PUNCTURE

• Type of Material: Article
• Authors: John Lyons, Emory University; Ching-Wen Chen, Emory University; Zhe Liang, Emory University; Wenxiao Zhang, Emory University; Eileen Burd, Emory University; Deena B. Chihade, Emory University; Alton Farris III, Emory University; Mandy Ford, Emory University; Craig Coopersmith, Emory University
• Language: English
• Date: 2019-06-01
• Publisher: Lippincott Williams & Wilkins
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2018 by the Shock Society
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1097/SHK.0000000000001203
• Title of Journal or Parent Work: Shock
• Volume: 51
• Issue: 6
• Start Page: 731
• End Page: 739
• Grant/Funding Information: his work was supported by funding from the National Institutes of Health (GM072808, GM095442, GM104323, GM109779, GM113228, GM117895)
• Keywords: Critically ill patients; mortality; Science & Technology; Life Sciences & Biomedicine; Disease tolerance; Septic shock; CD8 T cell; Cardiovascular System & Cardiology; intestine; Improves survival; Sepsis; Gut; Hematology; Lymphocyte apoptosis; Surgery; Peripheral Vascular Disease; Microenvironment; Mortality; General & Internal Medicine; sepsis; cell death; Outcomes; Critical Care Medicine; CD4 T cell; gut
• Research Categories: Biology, Cell; Health Sciences, Medicine and Surgery; Health Sciences, Health Care Management

Abstract

Patients with cancer who develop sepsis have a markedly higher mortality than patients who were healthy prior to the onset of sepsis. Potential mechanisms underlying this difference have previously been examined in two preclinical models of cancer followed by sepsis. Both pancreatic cancer/pneumonia and lung cancer/cecal ligation and puncture (CLP) increase murine mortality, associated with alterations in lymphocyte apoptosis and intestinal integrity. However, pancreatic cancer/pneumonia decreases lymphocyte apoptosis and increases gut apoptosis while lung cancer/CLP increases lymphocyte apoptosis and decreases intestinal proliferation. These results cannot distinguish the individual roles of cancer versus sepsis since different models of each were used. We therefore created a new cancer/sepsis model to standardize each variable. Mice were injected with a pancreatic cancer cell line and 3 weeks later cancer mice and healthy mice were subjected to CLP. Cancer septic mice had a significantly higher 10-day mortality than previously healthy septic mice. Cancer septic mice had increased CD4+ T cells and CD8+ T cells, associated with decreased CD4+ T cell apoptosis 24 h after CLP. Further, splenic CD8+ T cell activation was decreased in cancer septic mice. In contrast, no differences were noted in intestinal apoptosis, proliferation, or permeability, nor were changes noted in local bacterial burden, renal, liver, or pulmonary injury. Cancer septic mice thus have consistently reduced survival compared with previously healthy septic mice, independent of the cancer or sepsis model utilized. Changes in lymphocyte apoptosis are common to cancer model and independent of sepsis model, whereas gut apoptosis is common to sepsis model and independent of cancer model. The host response to the combination of cancer and sepsis is dependent, at least in part, on both chronic comorbidity and acute illness.