Article
Author: Freihammer, Max ; Nitz, Mark ; Heger, Jan-Michel ; Lange, Dinah ; Koker, Mirjam ; Nill, Marieke ; Balke-Want, Hyatt ; Ullrich, Roland T ; Knittel, Gero ; Büttner, Reinhard ; Peifer, Martin ; Propp, Jessica ; Baurmann, Herrad ; Simon, Adrian G ; Chmielewski, Markus ; Reinhardt, Hans Christian ; Riet, Tobias ; Brägelmann, Johannes ; Borchmann, Sven ; Hallek, Michael ; Persigehl, Thorsten ; Schleifenbaum, Julia K ; Gholamipoorfard, Rahil ; Häupl, Björn ; Jachimowicz, Ron D ; Potter, Nicole ; Stahl, David ; Jakob, Josefine ; Segbers, Paul ; Iuga, Andra-Iza ; Flümann, Ruth ; Bozek, Katarzyna ; Voltin, Conrad-Amadeus ; Abedpour, Nima ; Gregor, Lisa ; Oellerich, Thomas ; Rose, France ; Kobold, Sebastian ; Quaas, Alexander ; Pallasch, Christian ; Blakemore, Stuart J ; Borchmann, Peter ; Theobald, Sebastian J ; Tetenborg, Luis ; Merkelbach-Bruse, Sabine ; Wagener-Ryczek, Svenja ; Good, Zinaida ; Bachurski, Daniel ; Dörr, Janina ; Gödel, Philipp ; Rybniker, Jan ; Ludwig, Hanna ; Bröckelmann, Paul J ; Mackall, Crystal ; Schlözer, Lilli ; Müller, Werner
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 CSF1R+CD14+CD68+ 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 PGE2-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.