Biology subjects

Sen, T.

Publications and source records attributed to Sen, T..

7 recordsLinked to original sources

bioRxiv2022

Leveraging CD39 To Identify Tumor-Reactive CD8 T cells In Human Lung Cancer

The repertoire of tumor-infiltrating lymphocytes (TILs) can be vast, and many of these TILs are not endowed with tumor reactivity. While a number of reports have shown that tumor-reactive TILs express CD39, few reports have demonstrated that conversely, CD39 can be leveraged to serve as a proxy of tumor-reactive CD8 T cells. Using single-cell CITE/RNA/TCRseq, we show that CD39+ CD8 T cells in human lung cancers demonstrate transcriptional and proteomic features of exhaustion, tumor reactivity, and clonal expansion. Moreover, TCR cloning revealed that CD39 enriched for tumor-reactive CD8 T cell clones. Flow cytometry of 440 lung cancer specimens revealed that CD39 level on CD8 T cells is only weakly correlated with tumoral features that currently guide lung cancer therapy, such as histology, driver mutation, PD-L1 and tumor mutation burden. PD-1 axis blockade, but not cytotoxic chemotherapy, increased intratumoral CD39+ CD8 T cells. CD39 correlated with PD-1 expression on CD8 T cells and high pre-treatment/early-on-treatment levels were associated with improved clinical outcomes, but not immune-related adverse events, from immune checkpoint blockade therapy. This comprehensive profiling of the clinical, pathological and molecular features highlights the utility of CD39 as a proxy for tumor-reactive CD8 T cells in human lung cancer.

immunology↗

bioRxiv2021

Regulation of Neuroendocrine Plasticity by the RNA-Binding Protein ZFP36L1

Some small cell lung cancers (SCLCs) are highly sensitive to inhibitors of the histone demethylase LSD1. LSD1 inhibitors are thought to induce their anti-proliferative effects by blocking neuroendocrine differentiation, but the mechanisms by which LSD1 controls the SCLC neuroendocrine phenotype are not well understood. To identify genes required for LSD1 inhibitor sensitivity in SCLC, we performed a positive selection genome-wide CRISPR/Cas9 loss of function screen and found that ZFP36L1, an mRNA-binding protein that destabilizes mRNAs, is required for LSD1 inhibitor sensitivity. LSD1 binds and represses ZFP36L1 and upon LSD1 inhibition, ZFP36L1 expression is restored, which is sufficient to block the SCLC neuroendocrine differentiation phenotype and induce a non-neuroendocrine "inflammatory" phenotype. Mechanistically, ZFP36L1 binds and destabilizes SOX2 and INSM1 mRNAs, two transcription factors that are required for SCLC neuroendocrine differentiation. This work identifies ZFP36L1 as an LSD1 target gene that controls the SCLC neuroendocrine phenotype and demonstrates that modulating mRNA stability of lineage transcription factors controls neuroendocrine to non-neuroendocrine plasticity.

cancer biology↗

bioRxiv2021

Regional and clonal T cell dynamics at single cell resolution in immune checkpoint blockade

Paired T cell receptor and RNA single cell sequencing (scTCR/RNA-seq) has allowed for enhanced resolution of clonal T cell dynamics in cancer. Here, we report a scTCR/RNA-seq dataset of 162,062 single T cells from 31 tissue regions, including tumor, adjacent normal tissues, and lymph nodes (LN), from three patients who underwent resections for progressing lung cancers after immune checkpoint blockade (ICB). We found marked regional heterogeneity in tumor persistence that was associated with heterogeneity in CD4 and CD8 T cell phenotypes; regions with persistent cancer cells were enriched for follicular helper CD4 T cells (TFH), regulatory T cells (Treg), and exhausted CD8 T cells. Clonal analysis demonstrated that highly-expanded T cell clones were predominantly of the CD8 subtype, were ubiquitously present across all sampled regions, found in the peripheral circulation, and expressed gene signatures of large and dual-expanded clones that have been predictive of response to ICB. Longitudinal tracking of CD8 T cell clones in the peripheral blood revealed that the persistence of ubiquitous CD8 T cell clones, as well as phenotypically distinct clones with tumor-reactive features, correlated with systemic tumor control. Finally, tracking CD8 T cell clones across tissues revealed the presence of TCF-1+ precursor exhausted CD8 T cells in tumor draining LNs that were clonally linked to expanded exhausted CD8 T cells in tumors. Altogether, this comprehensive scTCR/RNA-seq dataset with regional, longitudinal, and clonal resolution provides fundamental insights into the tissue distribution, persistence, and differentiation trajectories of ICB-responsive T cells that underlie clinical responses to ICB.

immunology↗

bioRxiv2021

YfiB and the tripartite signaling system YfiBNR is involved in virulence of the gut invasive pathogen Shigella flexneri.

The intracellular pathogen Shigella flexneri, which is the causative agent of bacillary dysentery, significantly influences the worldwide implication of diarrheal infections, consequentially causing about 1.1 million deaths each year. Due to a non-availability of an authorized vaccine and the upsurge of multidrug resistance amongst Shigella strains, there has been a huge demand for further genetic analyses which could help in the advancement of new/improved drugs, and finding vaccine candidates against the pathogen. Whilst many features about the invasion of colonic cells by Shigella have been identified, fundamental gaps in information concerning in what way the bacteria transit, survive, and control gene expression, remain. The present study aims to illustrate the role of yfiB gene in Shigella virulence, which is a part of the periplasmic YfiBNR tripartite signaling system. This system is involved in the regulation of cyclic-di-GMP levels inside the bacterial cells, which is a vital messenger molecule impacting varied cellular processes such as biofilm formation, cytotoxicity, motility, synthesis of exopolysaccharide, and other virulence mechanisms like adhesion and invasion of the bacteria. Through a combination of genetic, biochemical, and virulence assays, we show how knocking out the yfiB gene can disrupt the entire YfiBNR system and affect biofilm formation, bacterial invasion, host-surface attachment, and the overall virulence of Shigella. This study eventually improves our understanding of the in-vivo persistence and survival of Shigella, brings light to the c-di-GMP lead regulation of Shigella virulence, and provides a prospective new target to design anti-infective drugs and vaccines against S. flexneri and other bacterial pathogens.

microbiology↗

bioRxiv2020

Multi-omic analysis of lung tumors defines pathways activated in neuroendocrine transformation

Lineage plasticity, a capacity to reprogram cell phenotypic identity under evolutionary pressure, is implicated in treatment resistance and metastasis in multiple cancers. In lung adenocarcinomas (LUADs) amenable to treatment with targeted inhibitors, transformation to an aggressive neuroendocrine (NE) carcinoma resembling small cell lung cancer (SCLC) is a recognized mechanism of acquired resistance. Defining molecular mechanisms of NE transformation in lung cancer has been limited by a paucity of well annotated pre- and post-transformation clinical samples. We hypothesized that mixed histology LUAD/SCLC tumors may capture cancer cells proximal to, and on either side of, histologic transformation. We performed detailed genomic, epigenomic, transcriptomic and proteomic characterization of combined LUAD/SCLC tumors as well as pre- and post-transformation clinical samples. Our data support that NE transformation is primarily driven by transcriptional reprogramming rather than mutational events. We identify genomic contexts in which NE transformation is favored, including frequent loss of the 3p chromosome arm in pre-transformation LUADs. Consistent shifts in gene expression programs in NE transformation include induction of several stem/progenitor cell regulatory pathways, including upregulation of PRC2 and WNT signaling, and suppression of Notch pathway activity. We observe induction of PI3K/AKT and an immunosuppressive phenotype in NE transformation. Taken together our findings define a novel landscape of potential drivers and therapeutic vulnerabilities of NE transformation in lung cancer.

cancer biology↗

bioRxiv2020

Single cell profiling reveals novel tumor and myeloid subpopulations in small cell lung cancer

Small cell lung cancer (SCLC) is an aggressive malignancy that includes subtypes defined by differential expression of ASCL1, NEUROD1, and POU2F3 (SCLC-A, -N, and -P, respectively), which are associated with distinct therapeutic vulnerabilities. To define the heterogeneity of tumors and their associated microenvironments across subtypes, we sequenced 54,523 cellular transcriptomes from 21 human biospecimens. Our single-cell SCLC atlas reveals tumor diversity exceeding lung adenocarcinoma, driven by canonical, intermediate, and admixed subtypes. We discovered a PLCG2-high tumor cell population with stem-like, pro-metastatic features that recurs across subtypes and predicts worse overall survival, and manipulation of PLCG2 expression in cells confirms correlation with key metastatic markers. Treatment and subtype are associated with substantial phenotypic changes in the SCLC immune microenvironment, with greater T-cell dysfunction in SCLC-N than SCLC-A. Moreover, the recurrent, PLCG2-high subclone is associated with exhausted CD8+ T-cells and a pro-fibrotic, immunosuppressive monocyte/macrophage population, suggesting possible tumor-immune coordination to promote metastasis.

cancer biology↗

bioRxiv2019

JBrowse Connect: A server API to connect JBrowse instances and users

We describe JBrowse Connect, an optional expansion to JBrowse that allows live messaging via WebSockets, notifications for new annotation tracks, heavy-duty analyses initiated by the user from within the browser, and other dynamic features. We present JBlast, an example application of JBrowse Connect that allows users to specify and execute BLAST searches, managed by a Galaxy instance, as well as tracking job progress and viewing results, all in the context of the browser.

bioinformatics↗