Spatial transcriptomics reveals distinct role of monocytes/macrophages with high FCGR3A expression in kidney transplant rejections

Yan Chen Wongworawat^1*Chirag Nepal²Mark Duhon³Wanqiu Chen²Minh-Tri Nguyen⁴Adam Godzik⁵Xinru Qiu⁵Wei Vivian Li⁶Gary Yu⁷Rafael Villicana⁴Craig Zuppan¹Michael De Vera⁴Mark Haas⁸Charles Wang^2*

• ¹Department of Pathology and Human Anatomy, Loma Linda University, Loma Linda, United States
• ²Center for Genomics, School of Medicine, Loma Linda University, Loma Linda, United States
• ³Technology Center for Genomics & Bioinformatics, Pathology & Laboratory Medicine, University of California Los Angeles, Los Angeles, United States
• ⁴Transplant Institute, Loma Linda University, Loma Linda, United States
• ⁵Division of Biomedical Sciences, University of California Riverside, Riverside, United States
• ⁶Department of Statistics, University of California Riverside, Riverside, United States
• ⁷Mailman School of Public Health, Columbia University, New York, United States
• ⁸Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, United States

Kidney transplant rejections are classified as active antibody mediated rejection (AMR) and cell mediated rejection (TCMR), with AMR primarily driven by antibodies produced by B cells, whereas TCMR is mediated by T lymphocytes that orchestrate cellular immune responses against the graft. Emerging evidence highlights the essential roles of innate immune cells in rejections, especially monocytes/macrophages and natural killer (NK) cells. However, the roles of specific innate immune cell subpopulations in kidney allograft rejection remain incompletely understood. Exploiting the spatial transcriptomics and formalin-fixed paraffin-embedded (FFPE) core needle biopsies from human kidney allografts, we demonstrated that non-rejection, AMR, acute TCMR and chronic active AMR have distinct transcriptomic features. Subclusters of monocytes/macrophages with high Fc gamma receptor IIIA (FCGR3A) expression were identified in C4d-positive active AMR and acute TCMR, and the spatial distribution of these cells corresponded to the characteristic histopathological features. Key markers related to monocyte/macrophage activation and innate alloantigen recognition were upregulated, along with metabolic pathways associated with trained immunity in AMR and TCMR. Taking together, these findings revealed that intragraft monocytes/macrophages with high FCGR3A expression play a critical role in kidney transplant rejections.