A recent study published in Cellular & Molecular Immunology unveils a novel approach to overcome lenalidomide resistance in follicular lymphoma (FL) by dual targeting of programmed death-ligand 1 (PD-L1) and 4-1BB. The research, led by investigators in China, identifies dendritic cells (DCs) as a critical microenvironmental factor contributing to disease progression in FL patients treated with rituximab plus lenalidomide (R2). The study provides a clinical rationale for dual targeting PD-L1 and 4-1BB in the chemo-free era of FL treatment.
Clinical Trial Findings
The phase 2 clinical trial (NCT03715309) enrolled 115 patients with newly diagnosed FL who received rituximab (375 mg/m2) and lenalidomide (25 mg daily for 10 days every 21 days). The results showed a complete remission (CR) rate of 76.5% and a partial remission (PR) rate of 12.2%. However, elevated serum β2-microglobulin (β2m) and lymph node size >6 cm were significantly associated with inferior progression-free survival (PFS) (P = 0.003 and P = 0.002, respectively), indicating these factors as predictors of disease progression in R2-treated FL patients.
Role of Dendritic Cells and PU.1
RNA-sequencing analysis revealed that relapse/progression patients had lower dendritic cell (DC) activity compared to non-relapse/progression patients (P = 0.030). Specifically, a decreased percentage of conventional DC 1 (cDC1) was observed in relapse/progression patients (P = 0.013). Further analysis identified the transcription factor PU.1 (SPI1) as significantly altered in cDC1-associated genes. In vitro experiments demonstrated that PU.1 regulates cDC1 maturation and function, contributing to lenalidomide resistance.
PU.1 Mediates Lenalidomide Resistance Through PD-L1 and 4-1BB
The study found that PU.1 expression is negatively correlated with PD-L1 (R = -0.473, P < 0.001) and positively correlated with 4-1BBL (R = 0.396, P = 0.003). Luciferase reporter assays confirmed that PU.1 downregulates transcriptional activity of PD-L1 and upregulates 4-1BBL. These findings suggest that PU.1 modulates the interaction between lymphoma cells and cDC1 through PD-1/PD-L1 and 4-1BB/4-1BBL pathways.
Dual Targeting PD-L1 and 4-1BB Counteracts PU.1-Mediated Alterations
To overcome PU.1-mediated cDC1 alterations, the researchers used a bi-specific PD-L1/4-1BB antibody. In vitro, the bi-specific antibody increased cDC1 cell numbers and maturation, and enhanced lymphoma cell autophagy in PU.1-knockdown cells. In vivo experiments using murine xenograft models showed that co-treatment with PD-L1 and 4-1BB antibody exhibited anti-lymphoma activity in PU.1-altered B-lymphoma cells, which conferred resistance to lenalidomide.
Clinical Implications
The study provides evidence that lenalidomide resistance mediated by PU.1 can be counteracted by bi-specific PD-L1/4-1BB antibody. "Dual targeting PD-L1 and 4-1BB antibody could thus be promising in the chemo-free era of FL treatment," the authors conclude. These findings suggest that combining immune checkpoint modulation with lenalidomide could be a promising immunotherapy strategy for overcoming resistance in FL treatment.
