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Extracellular vesicles and PD-L1 suppress macrophages inducing therapy resistance in TP53-deficient B-cell malignancies

Izquierdo, Elena ; Vorholt, Daniela ; Blakemore, Stuart ; Sackey, Benedict ; Nolte, Janica L. ; Barbarino, Verena ; Schmitz, Jan ; Nickel, Nadine ; Bachurski, Daniel ; Lobastova, Liudmila ; Nikolic, Milos ; Michalik, Michael ; Brinker, Reinhild ; Merkel, Olaf ; Franitza, Marek ; Georgomanolis, Theodoros ; Neuhaus, René ; Koch, Maximilian ; Nasada, Niklas ; Knittel, Gero ; Chapuy, Björn ; Ludwig, Nicole ; Meese, Eckart ; Frenzel, Lukas ; Reinhardt, Hans Christian ; Peifer, Martin ; Rebollido-Rios, Rocio ; Bruns, Heiko ; Krüger, Marcus ; Hallek, Michael ; Pallasch, Christian

Blood, 2022-06, Vol.139 (25), p.3617-3629 [Periódico revisado por pares]

Elsevier Inc

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Título:
Extracellular vesicles and PD-L1 suppress macrophages inducing therapy resistance in TP53-deficient B-cell malignancies
Autor: Izquierdo, Elena ; Vorholt, Daniela ; Blakemore, Stuart ; Sackey, Benedict ; Nolte, Janica L. ; Barbarino, Verena ; Schmitz, Jan ; Nickel, Nadine ; Bachurski, Daniel ; Lobastova, Liudmila ; Nikolic, Milos ; Michalik, Michael ; Brinker, Reinhild ; Merkel, Olaf ; Franitza, Marek ; Georgomanolis, Theodoros ; Neuhaus, René ; Koch, Maximilian ; Nasada, Niklas ; Knittel, Gero ; Chapuy, Björn ; Ludwig, Nicole ; Meese, Eckart ; Frenzel, Lukas ; Reinhardt, Hans Christian ; Peifer, Martin ; Rebollido-Rios, Rocio ; Bruns, Heiko ; Krüger, Marcus ; Hallek, Michael ; Pallasch, Christian
É parte de: Blood, 2022-06, Vol.139 (25), p.3617-3629
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
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Descrição: Genetic alterations in the DNA Damage Response (DDR) pathway are a frequent mechanism of resistance to CIT in B-cell malignancies. We have previously shown that the synergy of CIT relies on secretory crosstalk elicited by chemotherapy between the tumour cells and macrophages. Here, we show that loss of multiple different members of the DDR pathway inhibits macrophage phagocytic capacity in vitro and in vivo. Particularly loss of TP53 led to decreased phagocytic capacity ex vivo across multiple B-cell malignancies. We demonstrate via in vivo cyclophosphamide treatment using the Eµ-TCL1 mouse model that loss of macrophage phagocytic capacity in Tp53-deleted leukemia is driven by a significant downregulation of a phagocytic transcriptomic signature using scRNA-Seq. By analysing the tumour B-cell proteome, we identified a TP53 specific upregulation of proteins associated with extracellular vesicles (EV). We abrogated EV biogenesis in tumour B-cells via CRISPR-knockout (KO) of RAB27A and confirmed that the EVs from TP53-deleted lymphoma cells were responsible for the reduced phagocytic capacity and the in vivo CIT resistance. Furthermore, we observed that TP53 loss led to an upregulation of both PD-L1 cell surface expression and secretion of EVs by lymphoma cells. Disruption of EV bound PD-L1 by anti-PD-L1 antibodies or PD-L1 CRISPR-KO improved macrophage phagocytic capacity and in vivo therapy response. Thus, we demonstrate enhanced EV-release and increased PD-L1 expression in TP53-deficient B-cell lymphomas as novel mechanisms of macrophage function alteration in CIT resistance. This study indicates the use of checkpoint inhibition in the combination treatment of B-cell malignancies with TP53 loss.
Editor: Elsevier Inc
Idioma: Inglês

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Extracellular vesicles and PD-L1 suppress macrophages inducing therapy resistance in TP53-deficient B-cell malignancies

Elsevier Inc

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