Project description:In mouse models, the bromodomain PHD finger transcription factor (BPTF) chromatin remodeling subunit in tumor cells suppresses natural killer (NK) cell antitumor activity. In vitro, BPTF suppresses NK cell cytolytic activity to mouse and human cancer cell lines, demonstrating a conserved function.
Project description:We report an in situ vaccination, adaptable to nearly any type of cancer, that combines radiotherapy targeting one tumor and intratumoral injection of this site with tumor-specific antibody and interleukin-2 (IL-2; 3xTx). In a phase I clinical trial, administration of 3xTx (with an immunocytokine fusion of tumor-specific antibody and IL-2, hu14.18-IL2) to subjects with metastatic melanoma increases peripheral CD8+ T cell effector polyfunctionality. This suggests the potential for 3xTx to promote antitumor immunity against metastatic tumors. In poorly immunogenic syngeneic murine melanoma or head and neck carcinoma models, 3xTx stimulates CD8+ T cell-mediated antitumor responses at targeted and non-targeted tumors. During 3xTx treatment, natural killer (NK) cells promote CTLA4+ regulatory T cell (Treg) apoptosis in non-targeted tumors. This is dependent on NK cell expression of CD86, which is upregulated downstream of KLRK1. NK cell depletion increases Treg infiltration, diminishing CD8+ T cell-dependent antitumor response. These findings demonstrate that NK cells sustain and propagate CD8+ T cell immunity following 3xTx
Project description:Natural killer (NK) cell function is markedly impaired in acute leukemia patients, weakening their antitumor immune response; however, the specific mechanisms underlying these functional deficits remain incompletely understood. Here, we reveal the critical role of glutathione (GSH) metabolism in maintaining NK cell homeostasis and function. Compared with healthy individuals, NK cells from acute leukemia patients exhibit markedly reduced GSH levels. GSH depletion impairs NK cell cytotoxic activity, cytokine production, and proliferative capacity. Notably, supplementation with glutathione reduced ethyl ester (GSHEE) enhances the antileukemic activity of NK cells. Mechanistically, GSH supports optimal NK cell function by improving mitochondrial function and promoting oxidative phosphorylation (OXPHOS). In summary, this study identifies disrupted GSH metabolism as a driver of NK cell dysfunction in acute leukemia and suggests that GSH supplementation may enhance NK cell-mediated antileukemic effects, offering a potential new strategy for NK cell-based immunotherapy.
Project description:The importance of unanchored Ub in innate immunity has been shown only for a limited number of unanchored Ub-interactors. We investigated what additional cellular factors interact with unanchored Ub and whether unanchored Ub plays a broader role in innate immunity. To identify unanchored Ub-interacting factors from murine lungs, we used His-tagged recombinant poly-Ub chains as bait. These chains were mixed with lung tissue lysates and protein complexes were isolated with Ni-NTA beads. Sample elutions were subjected to mass spectrometry (LC-MSMS) analysis.