TY  - JOUR
A1  - Wu, Hao
A1  - Zhao, Xiufeng
A1  - Hochrein, Sophia M.
A1  - Eckstein, Miriam
A1  - Gubert, Gabriela F.
A1  - Knöpper, Konrad
A1  - Mansilla, Ana Maria
A1  - Öner, Arman
A1  - Doucet-Ladevèze, Remi
A1  - Schmitz, Werner
A1  - Ghesquière, Bart
A1  - Theurich, Sebastian
A1  - Dudek, Jan
A1  - Gasteiger, Georg
A1  - Zernecke, Alma
A1  - Kobold, Sebastian
A1  - Kastenmüller, Wolfgang
A1  - Vaeth, Martin
T1  - Mitochondrial dysfunction promotes the transition of precursor to terminally exhausted T cells through HIF-1α-mediated glycolytic reprogramming
JF  - Nature Communications
N2  - T cell exhaustion is a hallmark of cancer and persistent infections, marked by inhibitory receptor upregulation, diminished cytokine secretion, and impaired cytolytic activity. Terminally exhausted T cells are steadily replenished by a precursor population (Tpex), but the metabolic principles governing Tpex maintenance and the regulatory circuits that control their exhaustion remain incompletely understood. Using a combination of gene-deficient mice, single-cell transcriptomics, and metabolomic analyses, we show that mitochondrial insufficiency is a cell-intrinsic trigger that initiates the functional exhaustion of T cells. At the molecular level, we find that mitochondrial dysfunction causes redox stress, which inhibits the proteasomal degradation of hypoxia-inducible factor 1α (HIF-1α) and promotes the transcriptional and metabolic reprogramming of Tpex cells into terminally exhausted T cells. Our findings also bear clinical significance, as metabolic engineering of chimeric antigen receptor (CAR) T cells is a promising strategy to enhance the stemness and functionality of Tpex cells for cancer immunotherapy.
KW  - cytotoxic T cells
KW  - infection
KW  - lymphocyte differentiation
KW  - translational research
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-358052
VL  - 14
ER  - 
TY  - JOUR
A1  - Bachmann, Friederike
A1  - Schreder, Martin
A1  - Engelhardt, Monika
A1  - Langer, Christian
A1  - Wolleschak, Denise
A1  - Mügge, Lars Olof
A1  - Dürk, Heinz
A1  - Schäfer-Eckart, Kerstin
A1  - Blau, Igor Wolfgang
A1  - Gramatzki, Martin
A1  - Liebisch, Peter
A1  - Grube, Matthias
A1  - Metzler, Ivana v.
A1  - Bassermann, Florian
A1  - Metzner, Bernd
A1  - Röllig, Christoph
A1  - Hertenstein, Bernd
A1  - Khandanpour, Cyrus
A1  - Dechow, Tobias
A1  - Hebart, Holger
A1  - Jung, Wolfram
A1  - Theurich, Sebastian
A1  - Maschmeyer, Georg
A1  - Salwender, Hans
A1  - Hess, Georg
A1  - Bittrich, Max
A1  - Rasche, Leo
A1  - Brioli, Annamaria
A1  - Eckardt, Kai-Uwe
A1  - Straka, Christian
A1  - Held, Swantje
A1  - Einsele, Hermann
A1  - Knop, Stefan
T1  - Kinetics of renal function during induction in newly diagnosed multiple myeloma: results of two prospective studies by the German Myeloma Study Group DSMM
JF  - Cancers
N2  - Background: Preservation of kidney function in newly diagnosed (ND) multiple myeloma (MM) helps to prevent excess toxicity. Patients (pts) from two prospective trials were analyzed, provided postinduction (PInd) restaging was performed. Pts received three cycles with bortezomib (btz), cyclophosphamide, and dexamethasone (dex; VCD) or btz, lenalidomide (len), and dex (VRd) or len, adriamycin, and dex (RAD). The minimum required estimated glomerular filtration rate (eGFR) was >30 mL/min. We analyzed the percent change of the renal function using the International Myeloma Working Group (IMWG) criteria and Kidney Disease: Improving Global Outcomes (KDIGO)-defined categories. Results: Seven hundred and seventy-two patients were eligible. Three hundred and fifty-six received VCD, 214 VRd, and 202 RAD. VCD patients had the best baseline eGFR. The proportion of pts with eGFR <45 mL/min decreased from 7.3% at baseline to 1.9% PInd (p < 0.0001). Thirty-seven point one percent of VCD versus 49% of VRd patients had a decrease of GFR (p = 0.0872). IMWG-defined “renal complete response (CRrenal)” was achieved in 17/25 (68%) pts after VCD, 12/19 (63%) after RAD, and 14/27 (52%) after VRd (p = 0.4747). Conclusions: Analyzing a large and representative newly diagnosed myeloma (NDMM) group, we found no difference in CRrenal that occurred independently from the myeloma response across the three regimens. A trend towards deterioration of the renal function with VRd versus VCD may be explained by a better pretreatment “renal fitness” in the latter group.
KW  - multiple myeloma
KW  - renal failure
KW  - kidney
KW  - bortezomib
KW  - lenalidomide
KW  - induction regimen
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-234139
SN  - 2072-6694
VL  - 13
IS  - 6
ER  -