Macrophages are activated toward phagocytic lymphoma cell clearance by pentose phosphate pathway inhibition
Macrophages in the B cell lymphoma microenvironment represent a functional node in progression and therapeutic response. We assessed metabolic regulation of macrophages in the context of therapeutic antibody-mediated phagocytosis. Pentose phosphate pathway (PPP) inhibition induces increased phagocytic lymphoma cell clearance by macrophages in vitro, in primary human chronic lymphocytic leukemia (CLL) patient co-cultures, and in mouse models. Addition of the PPP inhibitor S3 to antibody therapy achieves significantly prolonged overall survival in an aggressive B cell lymphoma mouse model. PPP inhibition induces metabolic activation and pro-inflammatory polarization of macrophages while it decreases macrophages' support for survival of lymphoma cells empowering anti-lymphoma function. As a mechanism of macrophage repolarization, the link between PPP and immune regulation was identified. PPP inhibition causes decreased glycogen level and subsequent modulation of the immune modulatory uridine diphosphate glucose (UDPG)-Stat1-Irg1-itaconate axis. Thus, we hypothesize the PPP as a key regulator and targetable modulator of macrophage activity in lymphoma to improve efficacy of immunotherapies and prolong survival.
Authors
- Holger Winkels (ORCID: https://orcid.org/0000-0003-1333-2031)
- Jörn Meinel
- Reinhard Büttner (ORCID: https://orcid.org/0000-0001-8806-4786)
- Marcus Krüger (ORCID: https://orcid.org/0000-0002-5846-6941)
- Anna C. Beielstein (ORCID: https://orcid.org/0000-0001-7710-1377)
- Daniela Vorholt
- Paul Diefenhardt (ORCID: https://orcid.org/0000-0003-3982-8983)
- Janica L. Nolte
- Michael Michalik (ORCID: https://orcid.org/0000-0002-5932-5657)
- Stuart J. Blakemore (ORCID: https://orcid.org/0000-0003-2892-1162)
- Alma Villaseñor (ORCID: https://orcid.org/0000-0002-6652-2739)
- Jorge Sáiz (ORCID: https://orcid.org/0000-0003-1570-154X)
- Christian P. Pallasch (ORCID: https://orcid.org/0000-0001-5675-6905)
- Nadine Nickel (ORCID: https://orcid.org/0000-0002-0609-0735)
- Carolina Raíssa Costa Picossi
- Felix S.R. Picard (ORCID: https://orcid.org/0000-0001-7624-4704)
- Sebastian Brähler (ORCID: https://orcid.org/0000-0002-7685-5780)
- Michael J. Hallek (ORCID: https://orcid.org/0000-0002-7425-4455)
- Alexandra Florin (ORCID: https://orcid.org/0000-0002-2330-4176)
- Hans-Henrik Bartel
- Elena Izquierdo (ORCID: https://orcid.org/0000-0002-3355-2798)
- Coral Barbas (ORCID: https://orcid.org/0000-0003-4722-491X)
- Rebecca Linke
- Samruddhi Chawan
- Reinhild Brinker
- L Albert
Institutions
- Universidad San Pablo CEU (ES)
- University of Cologne (DE)
- Düsseldorf University Hospital (DE)
- Integrated Oncology (United States) (US)
- Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (DE)
- University Hospital Cologne (DE)
- Heinrich Heine University Düsseldorf (DE)
Publication Details
- Journal
- Cell Reports Medicine
- Published
- 2024-11-26
- DOI
- https://doi.org/10.1016/j.xcrm.2024.101830
- Citations
- 13
- Primary Topic
- Immune cells in cancer
- Type
- article
- Field-Weighted Citation Impact
- 3.13
Funders
- Gilead Sciences
- Deutsche Forschungsgemeinschaft
- José Carreras Leukämie-Stiftung
- Universität zu Köln