Biology subjects

Quevedo, R.

Publications and source records attributed to Quevedo, R..

7 recordsLinked to original sources

bioRxiv2026

Sequential infection reprograms the immune landscape to shape future responses

Mouse models have been instrumental in defining immune mechanisms but often fail to capture the complexity of human immunity, limiting clinical translation. A major limitation is the immunological immaturity of specific pathogen-free (SPF) mice relative to pathogen-experienced adult humans. Here, we use a sequential infection (SI) model that recapitulates cumulative pathogen exposure and define its impact on immune composition and function. Beyond the previously reported expansion of memory T cells, SI induced durable, system-wide remodeling across lymphoid and non-lymphoid tissues, reshaping innate and adaptive immune populations, tissue-resident immunity, and hematopoietic output. Single-cell transcriptomic analyses revealed inflammatory imprinting of naive CD4 and CD8 T cells, whereas memory T cells acquired enhanced effector programs coupled with reduced biosynthetic activity, transcriptional states that more closely resemble those of pathogen-experienced adult humans. Functionally, SI mice recapitulated the human response to anti-CD28 super-agonist and exhibited altered magnitude and differentiation of acute and chronic antiviral T cell responses, demonstrating that cumulative pathogen exposure reshapes both existing immunity and the generation of future immune responses. Thus, cumulative pathogen exposure coordinately remodels hematopoiesis and naive and memory lymphocyte states, establishing a durable inflammation-experienced immune landscape that reshapes both immune memory and future immune responses, with broad implications for the translational fidelity of preclinical mouse models.

immunology↗

bioRxiv2026

Functional Type I and Type II interferon crosstalk restricts progenitor exhausted CD8 T cells through spatial exclusion and checkpoint enforcement

Type I interferon (IFN-I) and interferon-{gamma} (IFN{gamma}) are central regulators of antiviral immunity, yet how they cooperatively govern CD8 T cell fate during chronic infection remains unresolved. Here, we uncover a previously unrecognized, spatially encoded interferon circuit that actively constrains progenitor exhausted CD8 T cells (Tpex) during chronic LCMV infection. Persistent IFN-I signaling indirectly restricts Tpex expansion by enforcing their sequestration within PDL1-rich B cell niches of lymphoid tissue and by suppressing T cell-derived IFN{gamma}. Blockade of IFN-I signaling enables Tpex migration into T cell zones of splenic follicles driving IFN{gamma} production, which in turn sustains PDL1 expression on myeloid cells to re-impose local inhibitory pressure. Combined IFN-I and IFN{gamma} blockade disrupts this feedback, promoting coordinated niche redistribution of Tpex and checkpoint remodeling that drives robust Tpex expansion. Single-cell transcriptomics reveal that this layered IFN-I-IFN{gamma} interplay establishes a regulatory balance that constrains Tpex proliferation while preserving effector-like transcriptional programs in their progeny effector CD8 T cells, ultimately preventing premature terminal differentiation. Thus, interferons orchestrate the coordinated T cell-myeloid regulatory circuit that integrates tissue organization, cytokine feedback, and checkpoint control to regulate CD8 T cell exhaustion during chronic infection.

immunology↗

bioRxiv2023

Dabrafenib alters MDSC differentiation and function by activation of GCN2

The effect of targeted therapeutics on anti-cancer immune responses is poorly understood. The BRAF inhibitor dabrafenib has been reported to activate the integrated stress response (ISR) kinase GCN2, and the therapeutic effect has been partially attributed to GCN2 activation. Since ISR signaling is a key component of myeloid-derived suppressor cell (MDSC) development and function, we measured the effect of dabrafenib on MDSC differentiation and suppressive activity. Our data showed that dabrafenib attenuated MDSC ability to suppress T cell activity, which was associated with a GCN2-dependent block of the transition from monocytic progenitor to polymorphonuclear (PMN)-MDSCs and proliferative arrest resulting in PMN-MDSC loss. Transcriptional profiling revealed that dabrafenib-driven GCN2 activation altered metabolic features in MDSCs enhancing oxidative respiration, and attenuated transcriptional programs required for PMN development. Moreover, we observed a broad downregulation of transcriptional networks associated with PMN developmental pathways, and increased activity of transcriptional regulons driven by Atf5, Mafg, and Zbtb7a. This transcriptional program alteration underlies the basis for PMN-MDSC developmental arrest, skewing immature MDSC development towards monocytic lineage cells. In vivo, we observed a pronounced reduction in PMN-MDSCs in dabrafenib-treated tumor-bearing mice suggesting that dabrafenib impacts MDSC populations systemically and locally, in the tumor immune infiltrate. Thus, our data reveals transcriptional networks that govern MDSC developmental programs, and the impact of GCN2 stress signaling on the innate immune landscape in tumors, providing novel insight into potentially beneficial off target effects of dabrafenib.

immunology↗

bioRxiv2023

EHMT2/G9a-Inhibition Reprograms Cancer-Associated Fibroblasts (CAFs) to a More Differentiated, Less Proliferative and Invasive State

Cancer-associated fibroblasts (CAFs) have previously been shown to play a pivotal role in multiple cancer dynamics, including mediating tumor cell invasion: their pro-invasive secretory profile and ability to remodel the extracellular matrix (ECM) architecture particularly promote tumor progression through tumor cell invasion into surrounding tissue areas and beyond. Given that reduced CAF abundance in tumors correlates with improved outcomes in various cancers, we set out to identify epigenetic targets involved in CAF activation in the tumor-stromal margin to reduce overall tumor aggressiveness. Using the GLAnCE (Gels for Live Analysis of Compartmentalized Environments) co-culture platform, we performed an image-based, phenotypic screen and identified EHMT2 (also known as G9a), an epigenetic enzyme that targets the methylation of histone 3 lysine 9 (H3K9), as the most potent modulator of CAF abundance and CAF-mediated tumor cell invasion. Transcriptomic and functional analysis of EHMT2-inhibited CAFs revealed the involvement of EHMT2 in driving CAFs towards a pro-invasive phenotype. Further, EHMT2 signaling mediated CAF hyperproliferation, a feature that is typically associated with activated fibroblasts present in tumors, but the molecular basis for which has not thus far been identified. This study suggests a role for EHMT2 as a regulator of CAF hyperproliferation within the tumor mass, which in turn magnifies CAF-induced pro-invasive effects on tumor cells.

cancer biology↗

bioRxiv2021

Non-coding mutations reveal cancer driver cistromes in luminal breast cancer

Whole genome sequencing of primary breast tumors enabled the identification of cancer driver genes 1,2 and non-coding cancer driver plexuses from somatic mutations 3-6. However, differentiating driver and passenger events among non-coding genetic variants remains a challenge to understand the etiology of cancer and inform delivery of personalized cancer medicine. Herein, we reveal an enrichment of non-coding mutations in cis-regulatory elements that cover a subset of transcription factors linked to tumor progression in luminal breast cancers. Using a cohort of 26 primary luminal ER+PR+ breast tumors, we compiled a catalogue of [~]100,000 unique cis-regulatory elements from ATAC-seq data. Integrating this catalogue with somatic mutations from 350 publicly available breast tumor whole genomes, we identified four recurrently mutated individual cis-regulatory elements. By then partitioning the non-coding genome into cistromes, defined as the sum of binding sites for a transcription factor, we uncovered cancer driver cistromes for ten transcription factors in luminal breast cancer, namely CTCF, ELF1, ESR1, FOSL2, FOXA1, FOXM1 GATA3, JUND, TFAP2A, and TFAP2C in luminal breast cancer. Nine of these ten transcription factors were shown to be essential for growth in breast cancer, with four exclusive to the luminal subtype. Collectively, we present a strategy to find cancer driver cistromes relying on quantifying the enrichment of non-coding mutations over cis-regulatory elements concatenated into a functional unit drawn from an accessible chromatin catalogue derived from primary cancer tissues.

cancer biology↗

bioRxiv2019

Karyotypic divergence confounds cellular phenotypes in large pharmacogenomic studies

BackgroundSomatic copy-number alterations that affect large genomic regions are a major source of genomic diversity in cancer and can impact cellular phenotypes. Clonal heterogeneity within cancer cell lines can affect phenotypic presentation, including drug response.\n\nMethodsWe aggregated and analyzed SNP and copy number profiles from six pharmacogenomic datasets encompassing 1,691 cell lines screened for 13 molecules. To look for sources of genotype and karyotype discordances, we compared SNP genotypes and segmental copy-ratios across 5 kb genomic bins. To assess the impact of genomic discordances on pharmacogenomic studies, we assessed gene expression and drug sensitivity data for compared discordant and concordant lines.\n\nResultsWe found 6/1,378 (0.4%) cell lines profiled in two studies to be discordant in both genotypic and karyotypic identity, 51 (3.7%) discordant in genotype, 97 (7.0%) discordant in karyotype, and 125 (9.1%) potential misidentifications. We highlight cell lines REH, NCI-H23 and PSN1 as having drug response discordances that may hinge on divergent copy-number q\n\nConclusionsOur study highlights the low level of misidentification as evidence of effective cell line authentication standards in recent pharmacogenomic studies. However, the proclivity of cell lines to acquire somatic copy-number variants can alter the cellular phenotype, resulting in a biological and predictable effects on drug sensitivity. These findings highlight the need for verification of cell line copy number profiles to inform interpretation of drug sensitivity data in biomedical studies.

cancer biology↗

bioRxiv2018

Genome analysis and data sharing informs timing of molecular events in pancreatic neuroendocrine tumour

Neuroendocrine tumours (NETs) are rare, slow growing cancers that present in a diversity of tissues. To understand molecular underpinnings of gastrointestinal (GINET) and pancreatic NETs (PNETs), we profiled 45 tumours combining exome, RNA, and shallow whole genome sequencing, as well as fluorescent in situ hybridization. In addition to expected somatic mutations and copy number alterations, we found that PNETs contained a highly consistent copy neutral loss-of-heterozygosity (CN-LOH) profile affecting over half of the genome; a greater percentage than any cancer analyzed to date. Our data indicates that onset of extreme autozygosity may be progressive, associated with metastasis, and initially triggered by the loss of DAXX/ATRX, and subsequent biallelic loss of MEN1. We confirmed this molecular timing model using targeted clinical sequencing data from an additional 43 NETs made available by the AACR GENIE project. Against this background of CN-LOH, several chromosomal regions consistently retained heterozygosity, suggesting selection for crucial allele-specific components specific to PNET progression and potential new therapeutic targets.\n\nStatement of significanceWe have discovered that pancreatic neuroendocrine tumours contain a characteristic pattern of copy neutral loss-of-heterozygosity affecting the majority of the genome following mutations of MEN1 and ATRX/DAXX. Against this background of loss-of-heterozygosity, specific genomic regions are consistently retained and may therefore contain vulnerable therapeutic targets for pancreatic neuroendocrine tumours.

cancer biology↗