Biology subjects

Tan, Y.-D.

Publications and source records attributed to Tan, Y.-D..

3 recordsLinked to original sources

bioRxiv2026

MicroRNA-29a enhances and preserves stem-like CD8 T cell differentiation by regulating master epigenetic circuits of exhaustion.

CD8 T cells mediate protective immune responses. However, persisting antigens such as chronic viruses or tumors redirect CD8 T cell differentiation to a sub-optimal, epigenetically defined state called exhaustion. Exhausted T cells (TEX) lose their ability to persist long-term and to initiate functional memory responses. Checkpoint inhibitor blockade temporarily restores effector functions, but immune reinvigoration is not long-lasting, due to the epigenetic stability of TEX. Therefore, epigenetic reprogramming of TEX leading to durable T cell responses is essential to improve disease control. Here, we demonstrate that a single microRNA (miR), miR-29a, epigenetically re-directs TEX differentiation and preserves TEX into a stem-like state, leading to long-term persisting progenitor TEX. MiR-29a rewires epigenetic maintenance programs, including downregulation of key exhaustion-associated regulators (Dnmt1, Dnmt3a, and Dnmt3b), alongside increased expression of progenitor- and stemness-associated genes such as Tcf7 and Il7r. These reprogrammed CD8 T cells are more sensitive to PD-L1 checkpoint blockade. Ectopic expression of miR-29a combined with aPD-L1 treatments enhances effector responses, while preserving T cell stemness. Together, our findings suggest that miR-29a can be leveraged to overcome current barriers to immune checkpoint blockade. HighlightsO_LIMiR-29a rewires key exhaustion-associated epigenetic maintenance programs, while enhancing stemness-associated transcriptional circuits. C_LIO_LIMiR-29a drives extensive remodeling of accessible chromatin in TEX. C_LIO_LIMiR-29a preserves newly generated progenitor TEX in a durable, epigenetically defined stem-like state with increased effector function. C_LIO_LIMiR-29a synergizes with aPD-L1; while miR-29a preserves progenitor TEX state, addition of aPD-L1 enhances the cytotoxic potential of these progenitor TEX cells. C_LI

immunology↗

bioRxiv2026

Tumor-suppressor signature for robust prognosis and prediction in adenocarcinoma non-small cell lung cancer

Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related mortality, partly due to limited early detection strategies and incomplete understanding of tumor-suppressive mechanisms. In our previous work, we identified 26 tumor suppressor (TS) genes and characterized their biological functions and regulatory networks. We systematically evaluated these TS genes across multiple microarray datasets by analyzing differential expression patterns, correlations with oncogenes, tumor-associated genes, and PD-1-related immune genes, as well as somatic mutation frequencies. A weighted scoring algorithm was used to construct a TS gene signature. Patients were stratified using z-score normalization, and univariable and multivariable Cox proportional hazards models were applied across multiple adenocarcinoma (ADC) cohorts. Prognostic performance was assessed using Kaplan-Meier analysis and AUC metrics. The 26 TS genes were consistently down-regulated in tumors and showed strong negative correlations with oncogenes, particularly in advanced stages. TS genes also exhibited stage-dependent correlations with PD-1-associated immune genes, with chemotaxis/cytokine-signaling genes behaving TS-like, while PDCD1 and SIT1 showed oncogene-like patterns. Somatic mutations were detected in only 32% of LUAD samples for TS genes, compared with 68% for oncogenes. Across seven independent ADC cohorts, high TS-signature expression was associated with significantly reduced risk of death and recurrence/relapse. The TS signature outperformed several published prognostic signatures and demonstrated robust predictive accuracy, with AUC values exceeding 0.7 in multiple datasets and >0.8 for relapse prediction in GSE30219. Across seven independent cohorts, high TS signature expression was consistently associated with significantly reduced risk of death or recurrence/relapse in ADC patients. Patients with high TS signature expression exhibited markedly improved survival probabilities compared with those with low expression. When benchmarked against several established prognostic signatures using AUC metrics, our TS signature demonstrated superior robustness and predictive accuracy for ADC prognosis.

cancer biology↗

bioRxiv2026

Archaic translation initiation factor eIF5B supports KSHV late lytic replication and viral oncogenesis by mimicking a hypoxic cellular landscape

Kaposis Sarcoma (KS) Herpesvirus (KSHV) is the etiological agent of KS, an AIDS-defining illness. Recent studies have demonstrated that even during normoxic conditions, KSHV facilitates replication by modulating hypoxia-inducible factors (HIFs), creating a hypoxia-like environment that promotes cellular transformation. KSHV lytic viral genes are favored for protein synthesis during infection by upregulating HIF2 and utilizing the hypoxic eIF4E2 translation initiation complex in oxygen-replete conditions. This translation initiation plasticity (TRIP) links viral replication strategies to angiogenic signaling and oncogenicity. However, the molecular basis of this plasticity remains poorly understood. This study reveals that viral inhibition of eukaryotic initiation factor 2 (eIF2) induces the use of another alternative initiation factor, eIF5B, which canonically mediates delivery of initiator methionine-tRNAiMet during hypoxia. We demonstrate through ribosome density fractionation that eIF2 accumulates in translationally inactive monosome fractions while eIF5B redistributes its translation activity toward polysomes during lytic replication. Progressive dependence on eIF5B during KSHV infection was illustrated by impaired late lytic gene expression, diminished virion production, and altered polysome profiles following eIF5B knockdown. Transcriptomic analyses further reveal that the mRNA landscape in KSHV-infected cells depleted of eIF5B mirrors that of uninfected hypoxic cells. Moreover, silencing of eIF5B in a natural infection model reduces both VEGF secretion and anchorage-independent growth--two hallmarks of KSHV viral oncogenicity. These results demonstrate that eIF5B functions as an essential component of alternative translation initiation machinery activated in response to eIF2 inactivation during KSHV lytic replication, emphasizing its key role in viral pathogenesis and its potential as a novel therapeutic target. IMPORTANCEKaposis Sarcoma Herpesvirus (KSHV) is a human cancer virus that causes severe malignancies in immunocompromised individuals, including the blood vessel cancer Kaposis Sarcoma and a highly aggressive body-cavity lymphoma. Although cells mount a response to infection by shutting down global protein synthesis, how viruses like KSHV continue making viral proteins when this cellular machinery is shutdown remains unclear. This study uncovers that KSHV exploits an ancient cellular factor typically used for protein production under low-oxygen conditions. We identify a previously unrecognized role for the translation factor, eIF5B, in supporting KSHV replication and select production of viral proteins during infection. Our work further demonstrates that KSHVs utilization of eIF5B contributes to a hypoxia-like environment during infection, ultimately contributing to cancer-promoting changes within the cell. These findings highlight a new strategy for tumor-virus reprogramming of host cells, opening an avenue for novel therapeutic targets to eliminate virus-associated cancers.

microbiology↗