CSF1R+ myeloid-monocytic cells drive CAR-T cell resistance in aggressive B cell lymphoma.
Abstract
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.
| Authors: | Stahl D, Gödel P, Balke-Want H, Gholamipoorfard R, Segbers P, Tetenborg L, Koker M, Dörr J, Gregor L, Bachurski D, Rose F, Simon AG, Good Z, Jakob J, Häupl B, Nill M, Flümann R, Riet T, Lange D, Blakemore SJ, Baurmann H |
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| Journal: | Cancer Cell . 2025 Aug 11;43(8):1476-1494.e10. doi: 10.1016/j.ccell.2025.05.013. |
| Year: | 2025 |
| PubMed: | PMID: 40513575 (Go to PubMed) |