Raekwon A. Williams
A5062546110- Immune cells in cancer
- Cancer, Hypoxia, and Metabolism
- Cancer Research and Treatments
- Epigenetics and DNA Methylation
- Bladder and Urothelial Cancer Treatments
- Immunotherapy and Immune Responses
- Ferroptosis and cancer prognosis
- Cancer, Lipids, and Metabolism
Bloomberg (United States)
2024
Johns Hopkins University
2022-2024
Johns Hopkins Medicine
2024
Sidney Kimmel Comprehensive Cancer Center
2024
University of Baltimore
2022-2023
Abstract Glutamine metabolism in tumor microenvironments critically regulates antitumor immunity. Using the glutamine-antagonist prodrug JHU083, we report potent growth inhibition urologic tumors by JHU083-reprogrammed tumor-associated macrophages (TAMs) and tumor-infiltrating monocytes. We show JHU083-mediated glutamine antagonism induced TNF, proinflammatory, mTORC1 signaling intratumoral TAM clusters. TAMs also exhibited increased cell phagocytosis diminished proangiogenic capacities. In...
<div>Abstract<p>Glutamine metabolism in tumor microenvironments critically regulates antitumor immunity. Using the glutamine-antagonist prodrug JHU083, we report potent growth inhibition urologic tumors by JHU083-reprogrammed tumor-associated macrophages (TAMs) and tumor-infiltrating monocytes. We show JHU083-mediated glutamine antagonism induced TNF, proinflammatory, mTORC1 signaling intratumoral TAM clusters. TAMs also exhibited increased cell phagocytosis diminished...
<div>Abstract<p>Glutamine metabolism in tumor microenvironments critically regulates antitumor immunity. Using the glutamine-antagonist prodrug JHU083, we report potent growth inhibition urologic tumors by JHU083-reprogrammed tumor-associated macrophages (TAMs) and tumor-infiltrating monocytes. We show JHU083-mediated glutamine antagonism induced TNF, proinflammatory, mTORC1 signaling intratumoral TAM clusters. TAMs also exhibited increased cell phagocytosis diminished...
<p>Supplementary file containing the figure legends for each of supplemental figures.</p>
<p>JHU083-induced glutamine antagonism causes extensive reprogramming of TILs. <b>A,</b> UMAP plot showing lymphocytic cell subsets identified from scRNA-seq analysis CD45<sup>+</sup> cells isolated B6CaP tumors (JHU083-treated vs. control). <b>B,</b> density plots all NK and T cells. <b>C,</b> Dot normalized expression selected marker genes in <b>A</b>. <b>D,</b> Changes proportions subsets, stem cell–like...
<p>Supplementary Figure 3</p>
<p>Supplementary Figure 2</p>
<p>Supplementary Figure 5</p>
<p>Supplementary Figure 6</p>
<p>Supplementary Figure 4</p>
<p>Supplementary Figure 1</p>
<p>The antitumor activity of the glutamine antagonist JHU083 against urologic tumors is myeloid dependent. <b>A,</b> Dot plots showing expression levels and fractional abundance cells expressing metabolism enzymes, <i>GLUL,</i> <i>GLS</i> across samples (tumor, involved, distal, benign). <b>B,</b> Violin different cell types <i>GLUL</i> <i>GLS</i>. Data for <b>A</b> <b>B</b> were generated...
<p>JHU083-mediated glutamine antagonism reprograms TME, differentially induces TAMs, TIMs, inflammatory TNF signaling and proliferation in TAMs/TIMs. <b>A,</b> UMAP stacked bar plots showing the diversity differential abundance of TAMs monocyte (TIM) clusters B6CaP tumors at an early point (day 7 posttreatment) using scRNA-seq (<i>n</i> = 6) across samples. UMAP, uniform manifold approximation projection for dimension reduction. <b>B,</b> Density...
<p>Supplementary Figure 2</p>
<p>JHU083-induced glutamine antagonism caused a divergent metabolic response affecting glycolysis, purine metabolism, and succinate in TAMs. <b>A</b> <b>B,</b> Surface intracellular expression of GLUT1 HKII (percentage positive population mean fluorescence intensity) on B6CaP-derived <b>C,</b> GSEA showing the enrichment Hallmark glycolysis gene set among DEGs bulk RNA-sequenced FACS-sorted TAMs following JHU083 treatment relative to control....
<p>JHU083-induced glutamine antagonism promotes phagocytosis of tumor cells by TAMs and decreases angiogenesis in the TME. <b>A,</b> Tumor volume measurement MB49 tumors different treatment conditions. JHU083 growth MB49-RFP<sup>+</sup> relative to nontreated (<i>n</i> = 5 or 6/group) tumors. <b>B,</b> Representative flow cytometry plots RFP<sup>+</sup> JHU083-treated vs. vehicle-treated <b>C,</b> Percentage within...
<p>Supplementary Figure 1</p>
<p>The antitumor activity of the glutamine antagonist JHU083 against urologic tumors is myeloid dependent. <b>A,</b> Dot plots showing expression levels and fractional abundance cells expressing metabolism enzymes, <i>GLUL,</i> <i>GLS</i> across samples (tumor, involved, distal, benign). <b>B,</b> Violin different cell types <i>GLUL</i> <i>GLS</i>. Data for <b>A</b> <b>B</b> were generated...
<p>JHU083-induced glutamine antagonism causes extensive reprogramming of TILs. <b>A,</b> UMAP plot showing lymphocytic cell subsets identified from scRNA-seq analysis CD45<sup>+</sup> cells isolated B6CaP tumors (JHU083-treated vs. control). <b>B,</b> density plots all NK and T cells. <b>C,</b> Dot normalized expression selected marker genes in <b>A</b>. <b>D,</b> Changes proportions subsets, stem cell–like...
<p>JHU083-induced glutamine antagonism promotes phagocytosis of tumor cells by TAMs and decreases angiogenesis in the TME. <b>A,</b> Tumor volume measurement MB49 tumors different treatment conditions. JHU083 growth MB49-RFP<sup>+</sup> relative to nontreated (<i>n</i> = 5 or 6/group) tumors. <b>B,</b> Representative flow cytometry plots RFP<sup>+</sup> JHU083-treated vs. vehicle-treated <b>C,</b> Percentage within...
<p>JHU083-induced glutamine antagonism affects tumor cell metabolism and induces death in urologic tumors. <b>A,</b> Log-fold changes of utilizing enzymes after JHU083 treatment vs. control tumors CD45<sup>−</sup> sorted cells from B6CaP tumors, followed by scRNA-seq. <b>B,</b> Western blot showing qualitative the levels synthesizing/utilizing transporters fraction MB49 <b>C,</b> Percentage GLUT1<sup>+</sup> live determined...
<p>JHU083-induced glutamine antagonism affects tumor cell metabolism and induces death in urologic tumors. <b>A,</b> Log-fold changes of utilizing enzymes after JHU083 treatment vs. control tumors CD45<sup>−</sup> sorted cells from B6CaP tumors, followed by scRNA-seq. <b>B,</b> Western blot showing qualitative the levels synthesizing/utilizing transporters fraction MB49 <b>C,</b> Percentage GLUT1<sup>+</sup> live determined...
<p>JHU083-mediated glutamine antagonism reprograms TME, differentially induces TAMs, TIMs, inflammatory TNF signaling and proliferation in TAMs/TIMs. <b>A,</b> UMAP stacked bar plots showing the diversity differential abundance of TAMs monocyte (TIM) clusters B6CaP tumors at an early point (day 7 posttreatment) using scRNA-seq (<i>n</i> = 6) across samples. UMAP, uniform manifold approximation projection for dimension reduction. <b>B,</b> Density...
<p>Supplementary Figure 3</p>