Izquierdo, Elena, Vorholt, Daniela, Blakemore, Stuart, Sackey, Benedict ORCID: 0000-0003-1016-7720, Nolte, Janica L., Barbarino, Verena, Schmitz, Jan, Nickel, Nadine, Bachurski, Daniel ORCID: 0000-0001-9168-9680, Lobastova, Liudmila, Nikolic, Milos, Michalik, Michael, Brinker, Reinhild, Merkel, Olaf, Franitza, Marek, Georgomanolis, Theodoros, Neuhaus, Rene, Koch, Maximilian, Nasada, Niklas, Knittel, Gero, Chapuy, Bjoern ORCID: 0000-0002-6485-8773, Ludwig, Nicole, Meese, Eckart, Frenzel, Lukas, Reinhardt, Hans Christian, Peifer, Martin ORCID: 0000-0002-5243-5503, Rebollido-Rios, Rocio, Bruns, Heiko, Krueger, Marcus, Hallek, Michael and Pallasch, Christian P. (2022). Extracellular vesicles and PD-L1 suppress macrophages, inducing therapy resistance in TP53-deficient B-cell malignancies. Blood, 139 (25). S. 3617 - 3630. WASHINGTON: AMER SOC HEMATOLOGY. ISSN 1528-0020

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Abstract

Genetic alterations in the DNA damage response (DDR) pathway are a frequent mechanism of resistance to chemoimmunotherapy (CIT) in B-cell malignancies. We have previously shown that the synergy of CIT relies on secretory crosstalk elicited by chemotherapy between the tumor 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 Em-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 small conditional RNA sequencing. By analyzing the tumor B-cell proteome, we identified a TP53-specific upregulation of proteins associated with extracellular vesicles (EVs). We abrogated EV biogenesis in tumor B-cells via clustered regularly interspaced short palindromic repeats (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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Izquierdo, ElenaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vorholt, DanielaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Blakemore, StuartUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sackey, BenedictUNSPECIFIEDorcid.org/0000-0003-1016-7720UNSPECIFIED
Nolte, Janica L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Barbarino, VerenaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmitz, JanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nickel, NadineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bachurski, DanielUNSPECIFIEDorcid.org/0000-0001-9168-9680UNSPECIFIED
Lobastova, LiudmilaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nikolic, MilosUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Michalik, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brinker, ReinhildUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Merkel, OlafUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Franitza, MarekUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Georgomanolis, TheodorosUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Neuhaus, ReneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Koch, MaximilianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nasada, NiklasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Knittel, GeroUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chapuy, BjoernUNSPECIFIEDorcid.org/0000-0002-6485-8773UNSPECIFIED
Ludwig, NicoleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Meese, EckartUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Frenzel, LukasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reinhardt, Hans ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Peifer, MartinUNSPECIFIEDorcid.org/0000-0002-5243-5503UNSPECIFIED
Rebollido-Rios, RocioUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bruns, HeikoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Krueger, MarcusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hallek, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pallasch, Christian P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-689148
DOI: 10.1182/blood.2021014007
Journal or Publication Title: Blood
Volume: 139
Number: 25
Page Range: S. 3617 - 3630
Date: 2022
Publisher: AMER SOC HEMATOLOGY
Place of Publication: WASHINGTON
ISSN: 1528-0020
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
CHRONIC LYMPHOCYTIC-LEUKEMIA; OPEN-LABEL; TUMOR; RITUXIMAB; CYCLOPHOSPHAMIDE; IMMUNOTHERAPY; FLUDARABINE; LYMPHOMA; BLOCKADE; EVASIONMultiple languages
HematologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/68914

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