Radulescu, C. | bioRxiv Science

bioRxiv2026

The differentiation and functional landscape of tumor-resident CD8⁺ T cells shapes immunity and clinical outcomes in clear cell renal cell carcinoma

Clear cell renal cell carcinoma (ccRCC) is a common and lethal kidney cancer in which CD8+ T cell-targeted immunotherapies are standard of care. However, tumor CD8+ T cell infiltration correlates with divergent clinical outcomes, reflecting functional heterogeneity. We comprehensively characterized tumor-specific memory CD8+ T cells in ccRCC using phenotypic, transcriptional and functional analyses. Three major subsets were identified based on tissue-residency markers: circulating (Tcirc), tissue-resident (Trm) and CD69+CD103- Trm-like cells, all recognizing autologous RCC cells in an HLA class I-dependent manner. Tcirc cells exhibited greater stemness and cytotoxic potential, whereas Trm populations displayed tissue-residency programs, enhanced tumor reactivity and exhaustion features. Single-cell transcriptomics analyses uncovered substantial heterogeneity within Trm cells, including progenitor, activated, transitional, type-17, interferon-responsive, regulatory and terminally exhausted states. Trajectory and TCR analyses indicated progressive differentiation from central-memory Tcirc cells toward tissue residency while losing circulation, cytotoxicity and stemness potentials and then progress toward terminal exhaustion. Enrichment of progenitor Trm cells associated with improved survival and favorable immunotherapy response, whereas regulatory or exhausted Trm cells correlated with poor outcomes. These findings define the differentiation and functional landscape of tumor-specific CD8+ T cells that shapes immunity and clinical outcomes in ccRCC.

immunology↗

bioRxiv2020

Ermin deficiency as an inside-out model of inflammatory dysmyelination

Ermin is an actin-binding protein found almost exclusively in the central nervous system (CNS) as a component of myelin sheaths. Although Ermin has been predicted to play a role in the formation and stability of myelin sheaths, this has not been directly examined in vivo. Here we show that Ermin is essential for myelin sheath integrity and normal saltatory conduction. Loss of Ermin in mice caused de-compacted and fragmented myelin sheaths and led to slower conduction along with progressive neurological deficits. RNA sequencing of the corpus callosum, the largest white matter structure in the CNS, pointed to inflammatory activation in aged Ermin-deficient mice, which was corroborated by increased levels of microgliosis and astrogliosis. The inflammatory milieu and myelin abnormalities were further associated with increased susceptibility to immune-mediated demyelination insult in Ermin knockout mice. Supporting a possible role of Ermin deficiency in inflammatory white matter disorders, a rare inactivating mutation in the ERMN gene was identified in multiple sclerosis patients. Our findings demonstrate a critical role for Ermin in maintaining myelin integrity. Given its near exclusive expression in myelinating oligodendrocytes, Ermin deficiency represents a compelling "inside-out" model of inflammatory dysmyelination and may offer a new paradigm for the development of myelin stability-targeted therapies.

neuroscience↗