Biology subjects

Nguyen, P. K.

Publications and source records attributed to Nguyen, P. K..

3 recordsLinked to original sources

bioRxiv2026

High-fat diet promotes exhaustion-associated T-cell remodeling across vascular and lymphoid tissues in atherosclerosis-prone mice

Background: Atherosclerosis is a chronic inflammatory disease driven by lipid accumulation and immune dysregulation. How chronic dietary lipid exposure reshapes T-cell states across vascular and lymphoid tissues, and whether these changes resolve after dietary normalization, remains incompletely defined. This study examined diet-associated T-cell remodeling and the contribution of macrophage-mediated stimulation. Methods: ApoE-deficient mice received a vegetarian diet (VD) or high-fat diet (HFD) for 12 or 24 weeks; a dietary reversal group received HFD for 12 weeks followed by VD for 12 weeks. CD45-positive cells from aorta, blood, spleen, lymph nodes, and bone marrow underwent single-cell RNA sequencing with matched T-cell receptor sequencing. T cell states were annotated using canonical markers, and exhaustion- and naive-associated programs were quantified using UCell scores. Analysis assessed T-cell composition, clonal expansion, and predicted macrophage-T cell communication, with splenic flow-cytometric validation. Results: HFD was associated with enrichment of exhaustion-associated states, with the highest exhaustion scores in the aorta. At 24 weeks, the pooled exhausted-cell proportion was 15.7% under HFD versus 10.6% under VD. Dietary reversal restored this proportion to 10.6%, while residual transcriptional changes persisted in a tissue-dependent manner. Flow cytometry corroborated increased inhibitory receptor expression and co-expression. Aortic macrophages exhibited inflammatory and antigen-presentation programs alongside increased predicted communication with T cells. Aortic T-cell activation and clonal expansion accompanied these changes, and clonotype size correlated with exhaustion score (Spearman correlation coefficient = 0.57, p = 0.029). Conclusion: Chronic HFD is associated with multicompartment T-cell remodeling, with prominent vascular exhaustion-associated programs and tissue-dependent recovery after dietary normalization. These findings suggest that dietary lipid exposure may leave a durable adaptive immune imprint across organs during atherosclerosis.

immunology↗

bioRxiv2024

Discovery of Novel, Potent and Orally Bioavailable SMARCA2 PROTACs with Synergistic Anti-tumor Activity in Combination with KRAS G12C Inhibitors.

Cancer genomic studies have identified frequent mutations in subunits of the SWI/SNF chromatin remodeling complex including SMARCA4 in non-small cell lung cancer with a frequency of up to 33% in advanced stage disease, making it the most frequently mutated complex in lung cancer. We and others have identified SMARCA2 to be synthetic lethal to SMARCA4, indicating SMARCA2 is a high value therapeutic target. Here, we disclose the discovery and characterization of potent, selective and orally bioavailable Cereblon-based SMARCA2 PROTACs. Biochemically, YDR1 and YD54 are potent SMARCA2 degraders with an average DC50 of 7.7nM and 3.5nM respectively in SMARCA4 mutant lung cancer cells. Phenotypically, both YDR1 and YD54 selectively inhibited growth of SMARCA4 mutant cancer cells. Further, we showed anti-tumor growth inhibitory activity of YDR1 and YD54 in SMARCA4 mutant xenograft models of lung cancer. Finally, we show that YDR1 and YD54 synergize with the KRAS G12C inhibitor sotorasib to inhibit growth of SMARCA4 and KRAS G12C co-mutant lung cancer cells. These findings provide additional evidence for the utility of single agent or combination regimens containing SMARCA2 PROTACs as synthetic lethal therapeutics against SMARCA4 mutant cancers.

cancer biology↗

bioRxiv2021

The role of antigen recognition in the γδ T cell response at the controlled stage of M. tuberculosis infection.

{gamma}{delta} T cells contribute to host immune defense uniquely; but how they function in different stages (e.g., acute versus chronic) of a specific infection remains unclear. As the role of{gamma}{delta} T cells in early, active Mycobacterium tuberculosis (Mtb) infection is well documented, we focused on elucidating the{gamma}{delta} T cell response in persistent or controlled Mtb infection. Systems analysis of circulating{gamma}{delta} T cells from a South African adolescent cohort identified a distinct population of CD8+{gamma}{delta} T cells that expanded in this state. These cells had features indicative of persistent antigenic exposure but were robust cytolytic effectors and cytokine/chemokine producers. While these{gamma}{delta} T cells displayed an attenuated response to TCR-mediated stimulation, they expressed Natural Killer (NK) cell receptors and had robust CD16 (Fc{gamma}RIIIA)-mediated cytotoxic response, suggesting alternative ways for{gamma}{delta} T cells to control this stage of the infection. Despite this NK- like functionality, the CD8+{gamma}{delta} T cells consisted of highly expanded clones, which utilized TCRs with different V{gamma}/{delta} pairs. Theses TCRs could respond to an Mtb-lysate, but not to phosphoantigens, which are components of Mtb-lysate that activate{gamma}{delta} T cells in acute Mtb infection, indicating that the CD8+{gamma}{delta} T cells were induced in a stage-specific, antigen-driven manner. Indeed, trajectory analysis showed that these{gamma}{delta} T cells arose from naive cells that had traversed distinct differentiation paths in this infection stage. Importantly, increased levels of CD8+{gamma}{delta} T cells were also found in other chronic inflammatory conditions, including cardiovascular disease and cancer, suggesting that persistent antigenic exposure may lead to similar{gamma}{delta} T cell responses.

immunology↗