Biology subjects

Darcy, P. W.

Publications and source records attributed to Darcy, P. W..

3 recordsLinked to original sources

bioRxiv2026

Colorectal cancers with distinct metastatic potential trigger divergent early T cell responses

Colorectal cancer (CRC) remains a leading cause of cancer mortality, with most cases refractory to immunotherapy. Distinguishing tumor-induced from steady-state mucosal T cell responses has been a critical barrier to understanding antitumor immunity in CRC. Using orthotopic transplantation of CRC organoids with and without metastatic potential, combined with temporal T cell fate-mapping, we show that non-metastatic tumors elicit early recruitment of CD8{beta} and CD4 T cells that acquired cytotoxic and Th1-like programs, whereas pro-metastatic tumors induce a naive-like, hypoactivated state. Tumor-infiltrating CD4+ T cells underwent clonal expansion, including clones recognizing microbial and dietary antigens. T cells in physical contact with tumor cells, identified by uLIPSTIC, were enriched for expanded and cytotoxic clones. Fate-mapped T cells from non-metastatic tumors suppressed tumor growth in an IFN-{gamma}-dependent manner, whereas pro-metastatic tumor-derived T cells failed to do so. Mechanistically, pro-metastatic tumors downregulated MHCII, and Ciita targeting in non-metastatic organoids reduced CD4 clonal expansion and led to tumor progression. Together, these findings define divergent early T cell trajectories associated with CRC metastatic potential, indicating that ineffective local immune engagement precedes metastatic dissemination.

immunology↗

bioRxiv2026

Eosinophil-epithelial interactions mediate protective intestinal remodeling during food allergy

Food allergies are associated with progressive gastrointestinal symptoms driven by exacerbated mucosal type-2 immunity. Here, we investigated whether cellular interactions between the gut epithelium and innate immune cells regulate the severity of allergic symptoms in mice. Using the BALB/c OVA-alum food allergy model, we observed that repeated oral allergen challenges remodel the gut epithelium, expanding tuft cells, while shifting the intestinal stem cell niche toward a fetal-like repair state. Using uLIPSTIC, we systematically characterized in vivo immune-epithelial interactions and found that eosinophils and mast cells directly interact with intestinal epithelial cells (iECs) in an allergen challenge-dependent manner. Epithelial subset-specific uLIPSTIC provided further resolution and revealed that eosinophils and mast cells contact enteroendocrine cells and Paneth cells in a regionally compartmentalized manner. Allergic challenge was associated with rapid eosinophil migration towards the crypts and modulation of iEC differentiation. Depletion of eosinophils using two independent approaches reversed key markers of food allergy-associated epithelial remodeling, while exacerbating allergic diarrhea and mortality from anaphylactic shock. These findings establish eosinophils as orchestrators of protective epithelial remodeling in food allergies.

immunology↗

bioRxiv2021

Vγ usage distinguishes pro- and anti-tumor intestinal γδ T cell subsets

{gamma}{delta} T cells physiologically scan the intestinal epithelium, representing a substantial fraction of infiltrating lymphocytes in colorectal cancer (CRC), albeit their role in CRC remains unclear. Using murine CRC models, we found that most {gamma}{delta} T cells in pre- or non-tumor colon express V{gamma}1+ or V{gamma}7+ and exhibit a cytotoxic profile. Targeting these {gamma}{delta} T cell subsets, as well as conditionally interfering with {gamma}{delta} T cell function at early stages of tumorigenesis led to heightened tumor development, suggesting anti-CRC functions for V{gamma}1+ and V{gamma}7+ subsets. In contrast, ROR{gamma}t+ {gamma}{delta} T cell subsets, including V{gamma}4+ and microbiotadependent V{gamma}6+, accumulated during CRC progression. Conditional deletion of ROR{gamma}t or V{gamma} chains revealed redundant roles for IL-17-producing V{gamma}4+ and V{gamma}6+ {gamma}{delta} T cells in promoting tumor growth. Our results uncover pro- and anti-tumor roles for {gamma}{delta} T cell subsets.

immunology↗