Preexisting malignancy abrogates the beneficial effects of CXCR4 blockade during sepsis

• Type of Material: Article
• Authors: Wenxiao Zhang, Emory University; Deena B Chihade, Emory University; Jianfeng Xie, Emory University; Ching-Wen Chen, Emory University; Kimberly M Ramonell, Emory University; Zhe Liang, Emory University; Craig Coopersmith, Emory University; Mandy Ford, Emory University
• Language: English
• Date: 2020-01-27
• Publisher: WILEY
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: ©2020 Society for Leukocyte Biology
• Final Published Version (URL): http://dx.doi.org/10.1002/JLB.3A1019-502R
• Title of Journal or Parent Work: JOURNAL OF LEUKOCYTE BIOLOGY
• Volume: 107
• Issue: 3
• Start Page: 485
• End Page: 495
• Grant/Funding Information: This work was supported by funding from the National Institutes of Health grants GM104323, GM109779, and GM113228 (to MLF and CMC), GM072808 and GM095442 (to CMC)
• Keywords: LUNG; BONE-MARROW; Science & Technology; chemokine receptors; Immunology; PROLIFERATION; Hematology; LYMPHOCYTE EGRESS; bone marrow; SEPTIC SHOCK; T-CELLS; SPHINGOSINE-1-PHOSPHATE; UP-REGULATION; Life Sciences & Biomedicine; MOBILIZATION; EXPRESSION; Sepsis; Cell Biology; T cell

Abstract

Patients with cancer are at an increased risk of developing and dying from sepsis. We previously reported that blockade of the chemokine receptor CXCR4 resulted in decreased CD4+ T cell exhaustion and improved survival in a model of polymicrobial sepsis in previously healthy mice. Here, we sought to determine whether CXCR4 blockade could improve mortality and immune dysregulation during sepsis complicated with malignancy. Results in animals inoculated with a lung cancer cell line and subjected to CLP 3 weeks later indicated that CXCR4 was up-regulated on naïve and central memory T cells following sepsis. Of note, and in contrast to results in previously healthy mice, CXCR4 blockade failed to improve survival in cancer septic animals; instead, it actually significantly worsened survival. In the setting of cancer, CXCR4 blockade failed to result in T cell egress from the bone marrow, reverse lymphopenia in the spleen, or reverse T cell exhaustion. Mechanistically, elevated expression of CD69 on naïve T cells in the bone marrow of cancer septic animals was associated with their inability to egress from the bone marrow in the setting of CXCR4 blockade. In conclusion, these results illuminate the differential impact of CXCR4 blockade on sepsis pathophysiology in the setting of cancer and highlight the need for personalized therapy during sepsis.