CSF1R(+) myeloid-monocytic cells drive CAR-T cell resistance in aggressive B cell lymphoma

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 PGE(2)-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.

• Stahl, D.
• Gödel, P.
• Balke-Want, H.
• Gholamipoorfard, R.
• Segbers, P.
• Tetenborg, L.
• Koker, M.
• Dörr, J.
• Gregor, L.
• Bachurski, D.
• Rose, F.
• Simon, A. G.
• Good, Z.
• Jakob, J.
• Häupl, B.
• Nill, M.
• Flümann, R.
• Riet, T.
• Lange, D.
• Blakemore, S. J.
• Baurmann, H.
• Voltin, C. A.
• Potter, N.
• Schlözer, L.
• Freihammer, M.
• Wagener-Ryczek, S.
• Iuga, A. I.
• Heger, J. M.
• Ludwig, H.
• Schleifenbaum, J. K.
• Propp, J.
• Bröckelmann, P. J.
• Jachimowicz, R. D.
• Knittel, G.
• Borchmann, S.
• Merkelbach-Bruse, S.
• Pallasch, C.
• Peifer, M.
• Rybniker, J.
• Quaas, A.
• Nitz, M.
• Brägelmann, J.
• Müller, W.
• Persigehl, T.
• Bozek, K.
• Theobald, S. J.
• Büttner, R.
• Oellerich, T.
• Hallek, M.
• Kobold, S.
• Chmielewski, M.
• Reinhardt, H. C.
• Mackall, C.
• Abedpour, N.
• Borchmann, P.
• Ullrich, R. T.