Characterizing the mechanistic role of TNF signaling via TNFR1 and TNFR2 on NK cell-mediated anti-tumor immunity 2859

Abstract Description Natural Killer (NK) cells are the main effector lymphocyte in innate immunity that possess exceptional abilities in detecting and eliminating cancer cells to disrupt cancer progression. However, NK cell cytotoxicity is modulated by the surrounding tumor microenvironment (TME). Pro-inflammatory cytokine, tumor necrosis factor (TNF), is often produced and secreted upon cancer progression which promotes local inflammation by binding to its receptors TNFR 1 or 2 that are differentially expressed across immune and non-immune cells. In our previous study, we have shown that TNFR1 accelerates cell death, while TNFR2 promote their effector functions. However, the effects of these receptors on NK cell anti-tumor capacities are still elusive. Using transgenic mice models with conditional deletion of TNFRs in NK cells, we investigated the impact of TNF on NK cell-mediated tumor surveillance and characterized the functional and phenotypic changes of TME-infiltrating NK cells via high dimensional flow cytometry. We found that Tnfr1 deficiency increased NK cell killing capacity in vitro and reduced tumor progression in vivo. In human NK cells, treatment with a TNFR2-specific agonist promoted NK cell proliferation and activation by upregulating proliferation, activation and immune checkpoint markers. Delineation of the roles of TNFR1 and TNFR2 on NK cells will be useful in informing the optimization and development of TNF- and NK cell-targeted cancer immunotherapy approaches. Funding Sources Supported by the Australian Government Research Training Program Scholarship, Metro South Health Research Support Scheme – Co-Funded Collaboration Grant (#RSS_2023_085) and Medical Research Future Fund in a co-funded partnership with the Queensland Children’s Hospital Foundation, Microba Life Sciences, Miltenyi Biotec, the Richie’s Rainbow Foundation, the Translational Research Institute, and UQ. Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)