Biology subjects

Lladser, A.

Publications and source records attributed to Lladser, A..

3 recordsLinked to original sources

bioRxiv2024

scExplorer: A Comprehensive Web Server for Single-Cell RNA Sequencing Data Analysis

Single-cell RNA sequencing (scRNA-seq) has redefined our ability to investigate cellular heterogeneity at unprecedented resolution. However, the computational analysis required for scRNA-seq data interpretation remains a significant barrier for many researchers. We present scExplorer, an interactive web application that streamlines the analysis workflow from preprocessing through dimensional reduction to differential expression analysis. The platform provides an intuitive interface for real-time data exploration and visualization while maintaining compatibility with established analysis frameworks in both R and Python environments. scExplorer significantly reduces the technical knowledge and computational requirements needed to perform scRNA-seq analysis, enabling researchers to focus on biological insights rather than computational complexity. The application modular design ensures scalability and robust performance, making it a valuable tool for both small-scale and large-scale single-cell studies. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=148 SRC="FIGDIR/small/622710v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@171afe8org.highwire.dtl.DTLVardef@d3b878org.highwire.dtl.DTLVardef@1f3fff1org.highwire.dtl.DTLVardef@285e95_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

bioRxiv2024

Long-term efficacy of adoptive cell therapy is determined by host CD8+ T cells and undermined by lymphodepleting preconditioning

Adoptive T cell therapy (ACT) has demonstrated remarkable efficacy in treating hematological cancers. However, its efficacy against solid tumors remains limited and the emergence of cancer cells that lose expression of targeted antigens often promotes resistance to ACT. Importantly, the mechanisms underlying effective and durable ACT-mediated tumor control are incompletely understood. Here, we show that adoptive transfer of TCR-transgenic CD8+ T cells eliminates established murine melanoma tumors, with concomitant accumulation of tumor-infiltrating CD8+ T cells exhibiting both progenitor-exhausted and terminally-differentiated phenotypes. Interestingly, host CD8+ T cells contributed to ACT-mediated elimination of primary tumors and rejected ACT-resistant melanoma cells lacking the targeted antigen. Mechanistically, ACT induced TNF-- and cross-presenting dendritic cell-dependent tumor accumulation of endogenous CD8+ T cells and effective tumor elimination. Importantly, although lymphodepleting preconditioning enhanced ACT-mediated tumor elimination, it abrogated host antitumor immunity and protection against ACT-resistant melanoma cells. Enrichment of transcriptional signatures associated with TNF- signaling, cross-presenting dendritic cells and tumor-specific CD8+ T cells in human melanoma tumors correlated with favorable responses to ACT and increased survival. Our findings reveal that long-term efficacy of ACT is determined by the interplay between transferred and endogenous CD8+ T cells and is undermined by lymphodepleting preconditioning, which ultimately favors ACT resistance.

immunology↗

bioRxiv2022

Nuanced role for dendritic cell intrinsic IRE1 RNase in the regulation of antitumor adaptive immunity.

The IRE1/XBPls axis of the unfolded protein response (UPR) plays divergent roles in dendritic cell (DC) biology in steady state versus tumor contexts. Whereas tumor associated DCs show dysfunctional IRE1/XBP1s activation that curtails their function, the homeostasis of conventional type 1 DCs (cDC1) in tissues requires intact IRE1 RNase activity. Considering that cDC1s are key orchestrators of antitumor immunity, it is relevant to understand the functional versus dysfunctional roles of IRE1/XBP1s in tumor DC subtypes. Here, we show that cDC1s constitutively activate IRE1 RNase within subcutaneous B16 melanoma and MC38 adenocarcinoma tumor models. Mice lacking XBP1s in DCs display increased melanoma tumor growth, reduced T cell effector responses and accumulation of terminal exhausted CD8+ T cells. Transcriptomic studies revealed that XBP1 deficiency in tumor cDCls decreased expression of mRNAs encoding XBPls and regulated IRE1 dependent decay (RIDD) targets. Finally, we find that the dysregulated melanoma growth and impaired T cell immunity noticed in XBP1 deficient mice are attributed to RIDD induction in DCs. This work indicates that IREl RNase activity in melanoma/MC38-associated DCs fine tunes aspects of antitumor immunity independently of XBP1s, revealing a differential role for the UPR axis that depends on the DC subtype and cancer model.

immunology↗