Macrophages are activated toward phagocytic lymphoma cell clearance by pentose phosphate pathway inhibition
Anna C. Beielstein, Elena Izquierdo, Stuart J. Blakemore, Nadine Nickel, Michael Michalik, Samruddhi Chawan, Reinhild Brinker, Hans-Henrik Bartel, Daniela Vorholt, L Albert, Janica L. Nolte, Rebecca Linke, Carolina Raíssa Costa Picossi, Jorge Sáiz, Felix S.R. Picard, Alexandra Florin, Jörn Meinel, Reinhard Büttner, Paul Diefenhardt, Sebastian Brähler, Alma Villaseñor, Holger Winkels, Michael Hallek, Marcus Krüger, Coral Barbas, Christian P. Pallasch
Abstract
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. • Macrophage-mediated lymphoma cell phagocytosis is increased by PPP inhibition • PPP inhibition is an immune-regulatory switch for macrophage function • PPP inhibition is linked to the modulation of the UDPG-Stat1-Irg1-itaconate axis • PPP inhibition is tolerable in vivo and boosts therapeutic B cell lymphoma targeting Beielstein et al. have shown that the metabolic inhibition of the pentose phosphate pathway in macrophages leads to increased macrophage activation, less lymphoma cell support, and increased antibody-dependent lymphoma cell clearance by macrophages. A significantly improved overall survival in a therapeutic lymphoma mouse model is achieved.