Leukemic cells proliferate faster than non-transformed counterparts. This requires them to change their metabolism to adapt to their high growth. This change can stress cells and facilitate recognition by immune cells such as cytotoxic lymphocytes, which express the activating receptor Natural Killer G2-D (NKG2D). The tumor suppressor gene p53 regulates cell metabolism, but its role in the expression of metabolism-induced ligands, and subsequent recognition by cytotoxic lymphocytes, is unknown. We show here that dichloroacetate (DCA), which induces oxidative phosphorylation (OXPHOS) in tumor cells, induces the expression of such ligands, e.g. MICA/B, ULBP1 and ICAM-I, by a wtp53-dependent mechanism. Mutant or null p53 have the opposite effect. Conversely, DCA sensitizes only wtp53-expressing cells to cytotoxic lymphocytes, i.e. cytotoxic T lymphocytes and NK cells. In xenograft in vivo models, DCA slows down the growth of tumors with low proliferation. Treatment with DCA, monoclonal antibodies and NK cells also decreased tumors with high proliferation. Treatment of patients with DCA, or a biosimilar drug, could be a clinical option to increase the effectiveness of CAR T cell or allogeneic NK cell therapies.
© 2022. The Author(s).

Premature senescence of renal tubular epithelial cell (RTEC), which is involved in kidney fibrosis, is a key event in the progression of diabetic nephropathy. However, the underlying mechanism remains unclear. Here we investigated the role and mechanism of decoy receptor 2 (DcR2) in kidney fibrosis and the senescent phenotype of RTEC. DcR2 was specifically expressed in senescent RTEC and associated with kidney fibrosis in patients with diabetic nephropathy and mice with streptozotocin-induced with diabetic nephropathy. Knockdown of DcR2 decreased the expression of α-smooth muscle actin, collagen I, fibronectin and serum creatinine levels in streptozotocin-induced mice. DcR2 knockdown also inhibited the expression of senescent markers p16, p21, senescence-associated beta-galactosidase and senescence-associated heterochromatic foci and promoted the secretion of a senescence-associated secretory phenotype including IL-6, TGF-β1, and matrix metalloproteinase 2 in vitro and in vivo. However, DcR2 overexpression showed the opposite effects. Quantitative proteomics and validation studies revealed that DcR2 interacted with peroxiredoxin 1 (PRDX1), which regulated the cell cycle and senescence. Knockdown of PRDX1 upregulated p16 and cyclin D1 while downregulating cyclin-dependent kinase 6 expression in vitro, resulting in RTEC senescence. Furthermore, PRDX1 knockdown promoted DcR2-induced p16, cyclin D1, IL-6, and TGF-β1 expression, whereas PRDX1 overexpression led to the opposite results. Subsequently, DcR2 regulated PRDX1 phosphorylation, which could be inhibited by the specific tyrosine kinase inhibitor genistein. Thus, DcR2 mediated the senescent phenotype of RTEC and kidney fibrosis by interacting with PRDX1. Hence, DcR2 may act as a potential therapeutic target for the amelioration of diabetic nephropathy progression.
Copyright © 2020 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Alcohol use disorder (AUD) involves dysregulation of innate immune signaling in brain. Toll-like receptor 3 (TLR3), an innate immune receptor that is upregulated in post-mortem human alcoholics, leads to induction of interferon (IFN) signaling. IFNs have been linked to depressive-like symptoms and therefore may play a role in addiction pathology. Astrocyte-neuronal signaling may contribute to maladaptation of neuronal circuits.
In this manuscript, we examine ethanol (EtOH) induction of IFN signaling in neuronal, astrocyte, and microglial cell lines and assess astrocyte-neuronal interactions.
U373 astrocytes, SH-SY5Y neurons, and BV2 microglia were treated with EtOH and analyzed for autocrine/paracrine IFN signaling.
EtOH induced TLR3, IFNβ, and IFNγ in SH-SY5Y neurons and U373 astrocytes, but not in BV2 microglia. The IFN response gene TRAIL was also strongly upregulated by TLR3 agonist Poly(I:C) and EtOH in U373 astrocytes. TRAIL blockage via neutralizing antibody prevented induction of IFNs in SH-SY5Y neurons but not in U373 astrocytes. Blocking TRAIL in conditioned media from EtOH-treated astrocytes prevented induction of IFNs in SH-SY5Y neurons. Finally, an in vivo model of chronic 10-day binge EtOH exposure in C57BL6/J mice, as well as single acute treatment with Poly(I:C), showed increased TRAIL +IR cells in both orbitofrontal and entorhinal cortex.
This study establishes a role of astrocyte to neuron TRAIL release in EtOH-induced IFN responses. This may contribute to alcohol associated negative affect and suggest potential therapeutic benefit of TRAIL inhibition in AUD.

Chimeric antigen receptor (CAR) T cell therapy is an effective method for treating specific cancers. CARs are normally designed to recognize antigens, which are highly expressed on malignant cells but not on T cells. However, when T cells are engineered with CARs that recognize antigens expressed on the T cell surface, CAR T cells exhibit effector function on other T cells, which results in fratricide, or killing of neighboring T cells. Here, using human leukocyte antigen-DR (HLA-DR)-targeted CAR T cells, we show that weak affinity between CAR and HLA-DR reduces fratricide and induces sustained CAR downregulation, which consequently tunes the avidity of CAR T cells, leading to desensitization. We further demonstrate that desensitized CAR T cells selectively kill Epstein-Barr virus-transformed B cells with enhanced HLA-DR expression, while sparing normal B cells. Our study supports an avidity-tuning strategy that permits sensing of antigen levels by CAR T cells.

Innate immune cells can sense hepatitis C virus (HCV)-infected cells and respond with anti-viral actions including secretion of interferons (IFNs). In previous studies, the response of individual innate immune cells against HCV was analyzed in detail. We hypothesized that interaction of multiple innate immune cells increases the magnitude of the immune response and eventually leads to clearance of HCV-infected cells. To investigate this, we co-cultured Huh-7 HCV subgenomic replicon (SGR) cells with peripheral blood mononuclear cells (PBMCs). We confirm secretion of IFNα by plasmacytoid dendritic cells (pDCs) and IFNγ by natural killer (NK) cells in the co-culture setup. Moreover, we observed that also monocytes contribute to the anti-viral response. Flow cytometry and ImageStream analysis demonstrated that monocytes take up material from HCV SGR cells in co-culture with PBMCs. Preceding the uptake, PBMCs caused apoptosis of HCV SGR cells by tumor necrosis factor-related apoptosis inducing ligand (TRAIL) expression on NK cells. We observed that only the interplay of monocytes, pDCs, and NK cells resulted in efficient clearance of HCV SGR cells, while these cell populations alone did not kill HCV SGR cells. Despite similar TRAIL receptor expression on Huh-7 control cells and HCV SGR cells, HCV activated PBMCs specifically killed HCV SGR cells and did not target Huh-7 control cells. Finally, we showed that HCV replicating cells per se are sensitive toward TRAIL-induced apoptosis. Our results highlight the importance of the interplay of different innate immune cells to initiate an efficient, rapid, and specific response against HCV-infected cells.