Torcasso, M. S. | Search bioRxiv

bioRxiv2026

Autoreactive antibody production by intrarenal B cells in mouse kidney allograft rejection

Antibody-mediated rejection (AMR) is a major cause of kidney allograft failure, with donor HLA-specific antibodies (DSA) recognized as primary drivers of AMR pathology. However, a significant proportion of AMR diagnoses lack detectable DSA, thus implicating DSA-independent mechanisms. In support, we previously reported on the accumulation of autoreactive B cells in rejecting renal biopsies, which raised the possibility that autoreactive IgG produced within the allograft contributes to graft pathology. In this study, we used mouse models to show that rejecting kidney allografts preferentially promoted a breach in autoreactive B cell tolerance, leading to the local production of autoreactive antibodies. Notably, autoreactive IgG responses were uncoupled from DSA production, indicative of distinct regulation. Organoid cultures confirmed that autoantibody production was observed in the rejecting kidney, whereas DSAs were produced in both the lymph node and graft. Intrarenal B cells expressing Nur77 were enriched for autoreactivity, consistent with in situ antigen recognition. Finally, autoreactive antibodies are pathogenic, since inhibiting autoantibody production with transient anti-IL-15 and CTLA-4Ig led to preserved kidney allografts. These unique features of in situ autoantibody responses may be relevant to diverse diseases with chronic tissue inflammation beyond transplantation.

immunology↗

bioRxiv2025

Spatially organized lymphocytic microenvironments in high grade primary prostate tumors

The spatial arrangement of immune cells in the tumor microenvironment (TME) varies widely, from dispersed to clustered and tumor excluded to infiltrating. Multiplexed spatial profiling is an effective means of characterizing tumor-infiltrating lymphocytes (TILs) and immune complexes such as tertiary lymphoid structures (TLS) in the TME. However, few approaches have been described for objectively parametrizing patterns of immune organization and assessing their association with biological or clinical variables. This makes it difficult to evaluate whether a set of tumors is relatively immunologically cold or hot. Here we describe an intuitive set of statistical tools (available in the R package, tlsR) for characterizing lymphocyte patterns in the TME of solid cancers. We apply tlsR to primary prostate cancer (PCa), which is often described as immunologically cold. Using a cohort of 29 radical prostatectomy specimens stratified into low Gleason-grade (LGG; n=15) and high Gleason-grades (HGG; n =14) we show that HGG PCa is significantly more infiltrated than LGG PCa with lymphocytes organized into B cell or T cell enriched immune clusters (BICs and TICs). A subset of these ICs have the B and T cell zonation and follicular dendritic cells characteristic of a bona fide TLS. HGGs are also enriched with ICs containing precursor exhausted T cells (Tpex) and proliferating B cells and their tumor compartments harbor granzyme-B+ cytotoxic T cells in contact with cancer cells. Thus, far from being cold, a subset of HGG PCa has features associated with active immune surveillance, a finding with implications for emerging PCa immunotherapies.

cancer biology↗