Biology subjects

Tat, C.

Publications and source records attributed to Tat, C..

3 recordsLinked to original sources

bioRxiv2025

A spatial atlas of chemoradiation therapy in pancreatic cancer identifies cellular and microenvironmental determinants of persister populations

The molecular pathways involved in the response to radiation therapy in pancreatic ductal adenocarcinoma (PDAC) remain poorly understood. We aimed to elucidate the adaptive mechanisms and cellular interactions within PDAC to radiation therapy (RT). We constructed a transcriptomic landscape of the cellular subtypes and spatially resolved neighborhoods from 50 patient samples, including 16 longitudinally matched single cell RNA sequencing and 34 spatial transcriptomics specimens. To resolve shortcomings of cell-type mixtures in spatial data, we developed a novel statistical method called SpaCCI (spatially aware analysis of cell-cell interactions) to profile cell-cell interactions and ligand-receptor enrichment. This revealed CXCL12/TGF{beta}-driven persister cell niches where activated fibroblasts reprogram tumor- associated macrophages and spatially exclude stress-response CD8 T cells after RT. Persister cancer cells displayed transcriptional evidence of recalcitrance to metal-induced cell death pathways of ferroptosis and cuproptosis which were recapitulated in preclinical models. Our study reveals the selective pressures experienced by PDAC following RT that may help provide insight for future multimodal therapeutic strategies.

cancer biology↗

bioRxiv2025

Tunneling CARs: Increasing CAR T tumor infiltration through the overexpression of MMP7 and SPP1

Chimeric antigen receptor T cell (CART) therapy has demonstrated remarkable efficacy in hematologic malignancies but has struggled to achieve comparable success in solid tumors. A key obstacle is the extracellular matrix (ECM) in solid tumors, which significantly impedes CART cell infiltration. In clinical trials, neuroblastoma (NB) has shown responsiveness to GD2-directed CART therapy, however, the failure of GD2.CARTs to effectively clear bulky disease - characterized by dense ECM - highlights the critical challenge of infiltration. In this study, we demonstrate that GD2.CARTs exhibit a unique infiltration-restriction compared to other CARTs and endogenous T cells. A separate analysis of clinical datasets identified MMP7 and SPP1 (OPN) as candidate genes to improve the infiltration of GD2.CARTs as these were upregulated in tumor-infiltrating leukocytes. MMP-7 and OPN overexpression enhanced CART extravasation (p < .001) and interstitial movement (p < .05) in ECM-dense environments in vitro. Overexpression of either OPN (p < .0001) or MMP-7 (p < .001) improved tumor infiltration in a xenograft model of NB. This resulted in improved tumor control (94% reduction in tumor burden, p < .05) and a survival extension in OPN-GD2.CART treated mice compared to unmodified GD2.CARTs (median of 148 days, p < .05). OPN overexpression did not increase off-target infiltration into healthy tissues or promote tumor metastasis, highlighting its potential for safe therapeutic application. Our study provides a framework for further exploration of gene modifications to improve CART infiltration and efficacy in solid tumors and identifies SPP1 as a candidate gene to improve GD2.CART treatment of bulky tumors.

immunology↗

bioRxiv2023

Regulation of Lung Immune Tone by the Gut-Lung Axis via Dietary Fiber, Gut Microbiota, and Short-Chain Fatty Acids

Lung immune tone, i.e. the immune state of the lung, can vary between individuals and over a single individuals lifetime, and its basis and regulation in the context of inflammatory responses to injury is poorly understood. The gut microbiome, through the gut-lung axis, can influence lung injury outcomes but how the diet and microbiota affect lung immune tone is also unclear. We hypothesized that lung immune tone would be influenced by the presence of fiber-fermenting short-chain fatty acid (SCFA)-producing gut bacteria. To test this hypothesis, we conducted a fiber diet intervention study followed by lung injury in mice and profiled gut microbiota using 16S sequencing, metabolomics, and lung immune tone. We also studied germ-free mice to evaluate lung immune tone in the absence of microbiota and performed in vitro mechanistic studies on immune tone and metabolic programming of alveolar macrophages exposed to the SCFA propionate (C3). Mice on high-fiber diet were protected from sterile lung injury compared to mice on a fiber-free diet. This protection strongly correlated with lower lung immune tone, elevated propionate levels and enrichment of specific fecal microbiota taxa; conversely, lower levels of SCFAs and an increase in other fatty acid metabolites and bacterial taxa correlated with increased lung immune tone and increased lung injury in the fiber-free group. In vitro, C3 reduced lung alveolar macrophage immune tone (through suppression of IL-1{beta} and IL-18) and metabolically reprogrammed them (switching from glycolysis to oxidative phosphorylation after LPS challenge). Overall, our findings reveal that the gut-lung axis, through dietary fiber intake and enrichment of SCFA-producing gut bacteria, can regulate innate lung immune tone via IL-1{beta} and IL-18 pathways. These results provide a rationale for the therapeutic development of dietary interventions to preserve or enhance specific aspects of host lung immunity.

immunology↗