Charlotte, F. | bioRxiv Science

bioRxiv2026

Morphologic intratumoral heterogeneity from routine whole-slide histopathology is prognostic for survival in primary central nervous system lymphoma: development in the LOC Network and international external validation

Background: Clinical scores incompletely capture outcomes in primary central nervous system lymphoma (PCNSL). We quantified morphologic heterogeneity in pretreatment hematoxylin and eosin (H\&E) whole slides. Patients and methods: Three independent cohorts of immunocompetent, HIV- and EBV-negative patients treated recently were analyzed: LOC 2023 (122 slides), phase III BLOCAGE-01 (245 slides; NCT02313389), and external Barcelona (BCN; 41 slides). UNI embeddings, prototype learning, spatial metrics, and elastic-net Cox regression defined ITH-C. Results: Models achieved bootstrap-corrected concordance of 0.797--0.834. Age-, sex-, and KPS-adjusted ITH-C HRs were 1.29 (95\% CI 1.01--1.64), 1.27 (1.07--1.51), and 2.13 (1.35--3.37), respectively. Adding ITH-C increased MSKCC C-index from 0.671 to 0.717, 0.560 to 0.593, and 0.588 to 0.706. Spatial transcriptomics linked ITH-C to immune programs. Conclusions: Routine H\&E encodes prognostic spatial heterogeneity in PCNSL. ITH-C complements clinical scores, supporting prospective risk stratification.

bioinformatics↗

bioRxiv2023

Altered X-chromosome inactivation predisposes to autoimmune manifestations in mice

In mammals, males and females show marked differences in immune responses. Males are globally more sensitive to infectious diseases while females are more susceptible to systemic autoimmunity. X-chromosome inactivation (XCI), the epigenetic mechanism that ensures the silencing of one X in females, may participate in these sex-biases. Here, we perturbed the expression of the trigger of XCI, the non-coding RNA Xist, in female mice. This resulted in reactivation of genes on the inactive X, including members of the Toll-like receptor 7 (TLR7) signalling pathway, in monocyte/macrophages, dendritic and B cells. Consequently, female mice spontaneously developed inflammatory signs typical of lupus, including anti-nucleic acid autoantibodies, increased frequencies of age-associated and germinal centre B cells and expansion of monocyte/macrophages and dendritic cells. Mechanistically, TLR7 signalling is dysregulated in macrophages, which leads to sustained expression of target genes upon stimulation. These findings provide a direct link between maintenance of XCI and female-biased autoimmune manifestations and highlight altered XCI as a cause of autoimmunity. TeaserThe reason why autoimmunity mostly affects women is unclear. Here, we show that aberrant expression of genes on the X induces signs of lupus in female mice.

immunology↗