Kley, A. L. | bioRxiv Science

bioRxiv2025

Regulatory T cells inhibit CD8+ TRM-like cells during the early stages of tumor immune escape

How the immune system surveys nascent tumors and how this surveillance is subverted remain poorly understood. Using high-plex cyclic immunofluorescence and 3D imaging, we identified regulatory T (Treg) cells that co-localize with tissue-resident memory (TRM)-like T cells in early-stage human melanoma. In an autochthonous Braf/PTEN melanoma model expressing a defined tumor antigen, the initial CD8+ T cell infiltrate adopts a CD103+CD101+ TRM-like fate, establishing active immunosurveillance within nascent lesions. TRM-like cells dominate early tumors, occupy a stable epidermal niche, express effector molecules, and initiate T cell recruitment. However, Treg cells adopt a parallel tissue-resident phenotype, co-localizing with TRM-like cells and restraining both cytotoxic and sentinel functions. Tumor-site-specific Treg depletion reactivated TRM-like cells, drove robust T cell recruitment, expanded tumor-specific responses, and limited tumor growth. These findings reveal how early immunosurveillance is established through tissue-resident programs and identify Treg co-option of this response as a critical mechanism of tumor immune evasion. One Sentence SummaryNascent melanoma imprints a tissue-resident program on the initial CD8+ T cell infiltrate, which is suppressed by regulatory T cells as a critical checkpoint in immune evasion.

immunology↗

bioRxiv2023

Resident memory T cell development is associated with AP-1 transcription factor upregulation across anatomical niches.

Tissue-resident memory T (TRM) cells play a central role in immune responses to pathogens across all barrier tissues after infection. However, the underlying mechanisms that drive TRM differentiation and priming for their recall effector function remains unclear. In this study, we leveraged both newly generated and publicly available single-cell RNA-sequencing (scRNAseq) data generated across 10 developmental time points to define features of CD8 TRM across both skin and small-intestine intraepithelial lymphocytes (siIEL). We employed linear modeling to capture temporally-associated gene programs that increase their expression levels in T cell subsets transitioning from an effector to a memory T cell state. In addition to capturing tissue-specific gene programs, we defined a consensus TRM signature of 60 genes across skin and siIEL that can effectively distinguish TRM from circulating T cell populations, providing a more specific TRM signature than what was previously generated by comparing bulk TRM to naive or non-tissue resident memory populations. This updated TRM signature included the AP-1 transcription factor family members Fos, Fosb and Fosl2. Moreover, ATACseq analysis detected an enrichment of AP-1-specific motifs at open chromatin sites in mature TRM. CyCIF tissue imaging detected nuclear co-localization of AP-1 members Fosb and Junb in resting CD8 TRM >100 days post-infection. Taken together, these results reveal a critical role of AP-1 transcription factor members in TRM biology and suggests a novel mechanism for rapid reactivation of resting TRM in tissue upon antigen encounter.

immunology↗