Stahl David, Gödel Philipp, Balke-Want Hyatt, Gholamipoorfard Rahil, Segbers Paul, Tetenborg Luis, Koker Mirjam, Dörr Janina, Gregor Lisa, Bachurski Daniel, Rose France, Simon Adrian G, Good Zinaida, Jakob Josefine, Häupl Björn, Nill Marieke, Flümann Ruth, Riet Tobias, Lange Dinah, Blakemore Stuart J, Baurmann Herrad, Voltin Conrad-Amadeus, Potter Nicole, Schlözer Lilli, Freihammer Max, Wagener-Ryczek Svenja, Iuga Andra-Iza, Heger Jan-Michel, Ludwig Hanna, Schleifenbaum Julia K, Propp Jessica, Bröckelmann Paul J, Jachimowicz Ron D, Knittel Gero, Borchmann Sven, Merkelbach-Bruse Sabine, Pallasch Christian, Peifer Martin, Rybniker Jan, Quaas Alexander, Nitz Mark, Brägelmann Johannes, Müller Werner, Persigehl Thorsten, Bozek Katarzyna, Theobald Sebastian J, Büttner Reinhard, Oellerich Thomas, Hallek Michael, Kobold Sebastian, Chmielewski Markus, Reinhardt Hans Christian, Mackall Crystal, Abedpour Nima, Borchmann Peter, Ullrich Roland T
Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; Else Kröner Forschungskolleg Clonal Evolution in Cancer, University Hospital Cologne, Cologne, Germany; Cancer Research Center Cologne Essen (CCCE), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Mildred Scheel School of Oncology Aachen Bonn Cologne Düsseldorf (MSSO ABCD), Faculty of Medicine and University Hospital of Cologne, Cologne, Germany.
Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; Cancer Research Center Cologne Essen (CCCE), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
Cancer Cell. 2025 Aug 11;43(8):1476-1494.e10. doi: 10.1016/j.ccell.2025.05.013. Epub 2025 Jun 12.
Despite the improvement, approximately 60% of patients with relapsed or refractory (r/r) aggressive B cell lymphoma (B-NHL) do not achieve durable benefit from CAR-T cell therapy. To elucidate factors associated with CAR-T therapy resistance, we conducted high-dimensional analyses of pre- and post-CAR-T cell specimens. In patients with non-durable response, we identified a prognostically relevant lymphoma-associated myeloid-monocytic (LAMM) gene signature. In-depth profiling revealed a distinct CSF1RCD14CD68 LAMM cell population in both human and murine B-NHL that inhibits CAR-T cell function and correlates with poor outcome. Cell-cell inference analysis uncovered that LAMM cells impair CAR-T cell function through a direct LAMM-T cell interaction via the PGE-EP2/EP4 axis. In an autochthonous lymphoma mouse model, combined anti-CD19 CAR-T cell therapy with CSF1R blockade exhibited synergistic effects and improved survival. These findings provide strong rationale for combining anti-CD19 CAR-T cells with CSF1R inhibitors in treating r/r aggressive B-NHL patients.
