Neutrophils in the tumor microenvironment (TME) induce T cell non-responsiveness characterized by a shift from proliferation and activation to lipid transport pathways
Year: 2023
Type: conference-abstract
Abstract: Circulating neutrophils (PMN) acquire a T cell suppressor function in the TME characterized by suppression of proliferation, cytokine, and metabolic responses in stimulated T cells. Using ovarian cancer ascites fluid supernatants (ASC) and malignant effusions from other solid tumors as authentic components of the TME, we have identified multiple PMN effector functions including complement signaling, CD11b/CD18 (CR3), and NADPH oxidase drive the suppressor phenotype. Activated PMN also cause CD11b-dependent trogocytosis of T cell membranes, causing membrane injury without inducing T cell apoptosis. We hypothesized that PMN-generated injury cues to T cells cumulatively result in non-responsiveness. We exposed healthy donor unstimulated or CD3/CD28-stimulated T cells to PMN, ASC, or PMN + ASC for 24h, then performed bulk RNA-seq on purified T cells. T cells exposed to PMN + ASC had severe suppression of pathways driving proliferation, protein synthesis, and metabolic pathways, but increased expression of genes associated with lipid and cholesterol transport to the plasma membrane, including CD36 and ATP binding cassettes. Consistent with these results, PMN +/− ASC induced significant upregulation of neutral lipid content on T cell membranes. Further analysis using a metabolism-specific transcriptional pipeline identified upregulation of fatty acid degradation pathways and transporters (CPT1A and SLC25A20). Though not well-studied in T cells, mobilization of lipids to the plasma membrane serves to repair membrane injury. Our results raise the notion that ASC-primed neutrophils induce non-responsiveness in T cells characterized by a shift from stimulated T cell activation to injury repair that enables T cell viability. NCI Grant Numbers: R01CA188900, R01CA267690
Source: The Journal of Immunology
Institutions: Roswell Park Comprehensive Cancer Center, Koch Institute for Integrative Cancer Research At MIT, Massachusetts Institute of Technology, National Institutes of Health, Beth Israel Deaconess Medical Center, Harvard University, National Cancer Institute, University at Buffalo, State University of New York
Language: English
Topic: Immune cells in cancer
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W4385686938