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  - Munawar, Umair
A1  - Zhou, Xiang
A1  - Prommersberger, Sabrina
A1  - Nerreter, Silvia
A1  - Vogt, Cornelia
A1  - Steinhardt, Maximilian J.
A1  - Truger, Marietta
A1  - Mersi, Julia
A1  - Teufel, Eva
A1  - Han, Seungbin
A1  - Haertle, Larissa
A1  - Banholzer, Nicole
A1  - Eiring, Patrick
A1  - Danhof, Sophia
A1  - Navarro-Aguadero, Miguel Angel
A1  - Fernandez-Martin, Adrian
A1  - Ortiz-Ruiz, Alejandra
A1  - Barrio, Santiago
A1  - Gallardo, Miguel
A1  - Valeri, Antonio
A1  - Castellano, Eva
A1  - Raab, Peter
A1  - Rudert, Maximilian
A1  - Haferlach, Claudia
A1  - Sauer, Markus
A1  - Hudecek, Michael
A1  - Martinez-Lopez, J.
A1  - Waldschmidt, Johannes
A1  - Einsele, Hermann
A1  - Rasche, Leo
A1  - Kortüm, K. Martin
T1  - Impaired FADD/BID signaling mediates cross-resistance to immunotherapy in Multiple Myeloma
JF  - Communications Biology
N2  - The treatment landscape in multiple myeloma (MM) is shifting from genotoxic drugs to immunotherapies. Monoclonal antibodies, immunoconjugates, T-cell engaging antibodies and CART cells have been incorporated into routine treatment algorithms, resulting in improved response rates. Nevertheless, patients continue to relapse and the underlying mechanisms of resistance remain poorly understood. While Impaired death receptor signaling has been reported to mediate resistance to CART in acute lymphoblastic leukemia, this mechanism yet remains to be elucidated in context of novel immunotherapies for MM. Here, we describe impaired death receptor signaling as a novel mechanism of resistance to T-cell mediated immunotherapies in MM. This resistance seems exclusive to novel immunotherapies while sensitivity to conventional anti-tumor therapies being preserved in vitro. As a proof of concept, we present a confirmatory clinical case indicating that the FADD/BID axis is required for meaningful responses to novel immunotherapies thus we report impaired death receptor signaling as a novel resistance mechanism to T-cell mediated immunotherapy in MM.
KW  - immunotherapy
KW  - translational research
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357609
VL  - 6
ER  -