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CSF-1R inhibition and lenalidomide synergize to promote myeloma control after autologous stem cell transplantation

ABSTRACT: Autologous stem cell transplantation (ASCT) with maintenance lenalidomide remains the mainstay of consolidation therapy for eligible multiple myeloma (MM) patients but preventing disease relapse remains a critical unmet need. Here we investigated whether immunosuppressive myeloid populations in bone marrow (BM) correlated with ASCT outcomes. Using a preclinical ASCT model with suboptimal endogenous anti-myeloma activity, we demonstrated that while neither CSF-1R inhibition nor lenalidomide monotherapy significantly improved outcomes, their combination synergistically attenuated disease progression and prolonged survival. Single-cell RNA sequencing revealed that lenalidomide expanded NK-like CD8+ T-cells but paradoxically also increased the frequency of Csf1r+ macrophages. Cell-cell communication analyses identified Csf1r+ macrophages as suppressors of these NK-like and effector-like exhausted (Tphex) CD8 T-cell populations through CD94/NKG2A and PD-L1/PD-1, respectively. CSF-1R blockade depleted these immunosuppressive macrophages, which correlated with decreased expression of inhibitory receptors and enhanced expression of activation markers in Tphex.

ORGANISM(S): Mus musculus

PROVIDER: GSE319792 | GEO | 2026/05/01

REPOSITORIES: GEO

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