Effects of in vivo CXCR4 blockade and proteasome inhibition on bone marrow plasma cells in HLA-sensitized kidney transplant candidates

• DOI: 10.1016/j.ajt.2023.02.022
• Publication Date: 2023-03-04T07:01:03Z
• Authors: Amy P. Rossi; Simon Tremblay; Cyd M. Castro-Rojas; Ashley A. Burg; Krishna M. Roskin; Jenna M. Gehman; Adele Rike-Shields; Rita R. Alloway; Paul Brailey; David Allman; David A. Hildeman; E. Steve Woodle
• Keywords: Proteasome Endopeptidase Complex; Receptors, CXCR4; Plasma Cells; Pilot Projects; Kidney Transplantation; Boronic Acids; Hematopoietic Stem Cell Mobilization; 3. Good health; Bortezomib; Mice; Bone Marrow; Heterocyclic Compounds; Pyrazines; Humans; Animals; Proteasome Inhibitors

To date, plasma cell (PC)-targeted therapies have been limited by suboptimal PC depletion and antibody rebound. We hypothesized this is partly because of PC residence in protective bone marrow (BM) microenvironments. The purpose of this proof-of-concept study was to examine the effects of the CXCR4 antagonist, plerixafor, on PC BM residence; its safety profile (alone and in combination with a proteasome inhibitor, bortezomib); and the transcriptional effect on BMPCs in HLA-sensitized kidney transplant candidates. Participants were enrolled into 3 groups: group A (n = 4), plerixafor monotherapy; and groups B (n = 4) and C (n = 4), plerixafor and bortezomib combinations. CD34+ stem cell and PC levels increased in the blood after plerixafor treatment. PC recovery from BM aspirates varied depending on the dose of plerixafor and bortezomib. Single-cell RNA sequencing on BMPCs from 3 group C participants pretreatment and posttreatment revealed multiple populations of PCs, with a posttreatment enrichment of oxidative phosphorylation, proteasome assembly, cytoplasmic translation, and autophagy-related genes. Murine studies demonstrated dually inhibiting the proteasome and autophagy resulted in greater BMPC death than did monotherapies. In conclusion, this pilot study revealed anticipated effects of combined plerixafor and bortezomib on BMPCs, an acceptable safety profile, and suggests the potential for autophagy inhibitors in desensitization regimens.