Biology subjects

Odunsi, K.

Publications and source records attributed to Odunsi, K..

7 recordsLinked to original sources

bioRxiv2023

Cancer relevance of circulating antibodies against LINE-1 antigens in humans

LINE-1 (L1), the most abundant family of autonomous retrotransposons occupying over 17% of human DNA, is epigenetically silenced in normal tissues but frequently derepressed in cancer, suggesting that L1-encoded proteins may act as tumor-associated antigens recognized by the immune system. Here, we established an immunoassay for detecting circulating autoantibodies against L1 proteins in human blood. Using this assay in >3,000 individuals with or without cancer, we observed significantly higher IgG titers against L1-encoded ORF1p and ORF2p in patients with lung, pancreatic, ovarian, esophageal, and liver cancers compared to healthy individuals. Remarkably, elevated levels of anti-ORF1p-reactive IgG were observed in cancer patients with disease stages 1 and 2, indicating that immune response to L1 antigens can occur at early phases of carcinogenesis. We conclude that the antibody response against L1 antigens could contribute to the diagnosis and determination of immunoreactivity of tumors among cancer types that frequently escape early detection.

cancer biology↗

bioRxiv2021

Indoleamine 2,3-dioxygenase upregulates PD-1 expression on ovarian tumor infiltrating CD8+ T cells via kynurenine activation of the aryl hydrocarbon receptor

The immunoregulatory enzyme, indoleamine 2,3-dioxygenase (IDO1) and the PD-1/PD-L1 axis are potent mechanisms that impede effective anti-tumor immunity in ovarian cancer. However, whether the IDO pathway regulates PD-1 expression in T cells is currently unknown. Here we show that tumoral IDO1 expression led to profound changes in tryptophan, nicotinate/nicotinamide, and purine metabolic pathways in the ovarian tumor microenvironment, and to an increased frequency of PD-1+CD8+ tumor infiltrating T cells. We determined that activation of the aryl hydrocarbon receptor (AHR) by kynurenine induced PD-1 expression, and this effect was significantly abrogated by the AHR antagonist CH223191. Mechanistically, kynurenine alters chromatin accessibility in regulatory regions of T cell inhibitory receptors, allowing AHR to bind to consensus XRE motifs in the promoter region of PD-1. These results enable the design of strategies to target the IDO1 and AHR pathways for enhancing anti-tumor immunity in ovarian cancer.

immunology↗

bioRxiv2020

CXCR6 governs the retention of tissue-resident memory T cells to promote enhanced surveillance and control of ovarian cancer

PurposeResident memory CD8 T cells owing to their ability to reside and persist in peripheral tissues, impart adaptive sentinel activity and amplify local immune response, have beneficial implications for tumor surveillance and control. The current study aims to clarify the less known chemotactic mechanisms that govern the localization, retention, and residency of memory CD8 T cells in the ovarian tumor microenvironment. Experimental DesignRNA/FACS based profiling of chemokine receptor expression in CD8+ resident memory T cells in human ovarian cancer and analyze their association with survival. Analyze chemokine receptor role in anti-tumor response and control by resident memory T cells using prophylactic mice models of ovarian cancer, treated with adoptive transfer of OT1 T cells and vaccination with maraba virus-OVA to target Ovalbumin expressing tumor. ResultsChemokine receptor profiling of CD8+CD103+ resident memory TILs in ovarian cancer patients revealed high expression of CXCR6. Analysis of the TCGA ovarian cancer database revealed CXCR6 to be associated with CD103 and increased patient survival. Functional studies in mouse models of ovarian cancer revealed that CXCR6 is a marker of resident, but not circulatory tumor-specific memory CD8 T cells. Knockout of CXCR6 in tumor-specific CD8 T cells showed reduced retention in tumor tissues leading to diminished resident memory responses and poor control of ovarian cancer ConclusionsCXCR6 by promoting increased retention in tumor tissues serves a critical role in resident memory T cell-mediated immunosurveillance and control of ovarian cancer. Future studies warrant exploiting CXCR6 to promote resident memory response in cancers.

immunology↗

bioRxiv2020

A circulating T-cell differentiation marker to predict response to immune checkpoint inhibitors

Immune checkpoint inhibitors (ICI) have revolutionized treatment for various cancers; however, durable response is limited to only a subset of patients. Discovery of blood-based biomarkers that reflect dynamic change of the tumor microenvironment, and predict response to ICI will markedly improve current treatment regimens. Here, we investigated a role of CX3C chemokine receptor 1 (CX3CR1), a marker of T-cell differentiation, in predicting response to ICI therapy. Successful treatment of tumor-bearing mice with ICI increased the frequency and T-cell receptor clonality of the peripheral CX3CR1+CD8+ T-cell subset that included an enriched repertoire of tumor-specific and tumor-infiltrating CD8+ T cells. Furthermore, an increase in the frequency of the CX3CR1+ subset in circulating CD8+ T cells early after initiation of anti-PD-1 therapy correlated with response and survival in patients with non-small cell lung cancer (NSCLC). Taken together, these data support T-cell CX3CR1 expression as a blood-based dynamic biomarker to predict response to ICI therapy.

immunology↗

bioRxiv2020

RNA editing enzyme APOBEC3A promotes pro-inflammatory (M1) macrophage polarization

Pro-inflammatory (M1) macrophage polarization is associated with microbicidal and antitumor responses. We recently described APOBEC3A-mediated cytosine-to-uracil (C>U) RNA editing during M1 polarization. However, the functional significance of this editing is unknown. Here, we find that APOBEC3A-mediated cellular RNA editing can also be induced by influenza or Maraba virus infections of normal human macrophages, and by interferons in tumor-associated macrophages. Gene knockdown and RNA_Seq analyses show that APOBEC3A mediates C>U RNA editing of 209 exonic/UTR sites in 203 genes during M1 polarization. The highest level of deleterious C>U RNA editing occurred in THOC5, encoding a nuclear mRNA export protein implicated in M-CSF-driven macrophage differentiation. Knockdown of APOBEC3A reduces pro-inflammatory M1 markers including IL6, IL23A and IL12B gene expression, CD86 surface protein expression, and TNF-, IL-1{beta} and IL-6 cytokine secretion, and increases glycolysis and glycolytic capacity. Thus, APOBEC3A cytidine deaminase plays an important role in transcriptomic and functional polarization of M1 macrophages.

immunology↗

bioRxiv2019

Extensive Intratumor Proteogenomic Heterogeneity Revealed by Multiregion Sampling in a High-Grade Serous Ovarian Tumor Specimen

Enriched tumor epithelium, tumor-associated stroma, and whole tissue were collected by laser microdissection from thin sections across spatially separated levels of ten primary high-grade serous ovarian tumors and analyzed using proteomics (mass spectrometry and reverse phase protein microarray) and RNA-sequencing analyses. Comparative analyses of transcript and protein abundances revealed independent clustering of enriched stroma and enriched tumor epithelium, with whole tumor tissue clustering between purified collections, driven by overall tumor purity. Comparison of historic prognostic molecular subtypes for HGSOC revealed protein and transcript expression from tumor epithelium correlated most strongly with the differentiated molecular subtype, whereas stromal proteins and transcripts most strongly correlated with mesenchymal subtype. Protein and transcript abundance in tumor epithelium and stromal collections from neighboring sections exhibited decreased correlation in samples collected just hundreds of microns apart. These data reveal substantial protein and transcript expression heterogeneity within the tumor microenvironment that directly bears on prognostic signatures and underscore the need to enrich cellular subpopulations for expression profiling.

cancer biology↗

bioRxiv2019

Co-regulation and functional cooperativity of FOXM1 and RHNO1 bidirectional genes in ovarian cancer

We report that the oncogenic transcription factor FOXM1 is arranged in a head-to-head configuration with RHNO1, a gene involved in the ATR/CHK1-dependent DNA replication stress (DRS) response. FOXM1 and RHNO1 are both amplified and upregulated in high-grade serous ovarian cancer (HGSC). FOXM1 and RHNO1 expression are closely associated in normal and cancer tissues, including single cells, and a bidirectional promoter (F/R-BDP) mediates balanced expression. Targeting of FOXM1 and RHNO1 in HGSC cells using shRNA, CRISPR mutagenesis, or CRISPR interference directed to the F/R-BDP reduced DNA homologous recombination repair (HR) capacity, increased DNA damage, reduced clonogenic survival, and sensitized HGSC cells to the poly-ADP ribosylase inhibitor (PARPi) olaparib. Thus, there is functional cooperativity between FOXM1 and RHNO1 in cancer cells, and combinatorial targeting of this bidirectional gene pair may be a novel cancer therapeutic strategy. More broadly, our data provide evidence that bidirectional gene units function in human cancer.

cancer biology↗