Dual targeting PD-L1 and 4-1BB to overcome dendritic cell-mediated lenalidomide resistance in follicular lymphoma.

in Signal transduction and targeted therapy by Zhong Zheng, Jian-Biao Wang, Rui Sun, Nan Wang, Xiang-Qin Weng, Tian-Yuan Xu, Di Fu, Yan Feng, Peng-Peng Xu, Shu Cheng, Li Wang, Yan Zhao, Bin Qu, Chuan-Xin Huang, Wei-Li Zhao

TLDR

  • The study evaluated the efficacy and safety of rituximab plus lenalidomide in newly diagnosed FL patients and identified PU.1 as a key regulator of immunomodulatory effects.
  • Findings suggest that dual targeting of PD-L1 and 4-1BB could be an alternative immunotherapeutic strategy in FL treatment.

Abstract

Immunomodulatory agent lenalidomide is effective in treating follicular lymphoma (FL). We conducted the first trial of immunotherapy rituximab plus lenalidomide in newly diagnosed FL in China (NCT03715309). One-hundred and fifteen patients were enrolled and treated with rituximab 375 mg/mintravenously on day 0 and lenalidomide 25 mg orally on day 1-10 for 6 cycles of induction treatment, as well as lenalidomide for 6 cycles and rituximab for 8 cycles of maintenance treatment. We found that inferior progression-free survival of the patients was significantly associated with elevated serum β2m and lymph node >6 cm, linking to decreased lymphoma cell autophagy and dendritic cell infiltration within the tumor microenvironment. PU.1 transcriptionally downregulated PD-L1 (Programmed death ligand 1) expression and upregulated 4-1BBL (4-1BB ligand) expression, increased lymphoma cell autophagy and dendritic cell maturation via PD-1/PD-L1 and 4-1BB/4-1BBL interaction. In vitro in co-culture system and in vivo in murine xenograft model, knockdown of PU.1 induced lenalidomide resistance, but sensitized FL cells to bi-specific PD-L1/4-1BB antibody or combined treatment of PD-L1 inhibitor and 4-1BB agonist. Collectively, PU.1 is essential in immunomodulatory effect of FL through PD-1/PD-L1- and 4-1BB/4-1BBL-mediated microenvironmental modulation. Dual targeting PD-L1 and 4-1BB could be an alternative immunotherapeutic strategy in the chemo-free era of FL treatment.

Overview

  • The first trial of immunotherapy rituximab plus lenalidomide was conducted in newly diagnosed follicular lymphoma (FL) patients in China.
  • The study aimed to evaluate the efficacy and safety of the combination therapy and identify potential predictive biomarkers for treatment outcomes.
  • One-hundred and fifteen patients were enrolled and treated with the combination therapy for 6 cycles of induction and 6 cycles of maintenance treatment.

Comparative Analysis & Findings

  • Elevated serum β2m and lymph node size greater than 6 cm were significantly associated with inferior progression-free survival and decreased lymphoma cell autophagy and dendritic cell infiltration.
  • PU.1 transcriptionally downregulated PD-L1 expression and upregulated 4-1BBL expression in FL cells, regulating lymphoma cell autophagy and dendritic cell maturation.
  • In vitro and in vivo studies showed that knockdown of PU.1 induced lenalidomide resistance, but sensitized FL cells to bi-specific PD-L1/4-1BB antibody or combined treatment of PD-L1 inhibitor and 4-1BB agonist.

Implications and Future Directions

  • The study suggests that dual targeting of PD-L1 and 4-1BB could be an alternative immunotherapeutic strategy in the chemo-free era of FL treatment.
  • Further studies are needed to evaluate the efficacy and safety of this combination therapy in larger cohorts and to identify potential predictive biomarkers for treatment outcomes.
  • The study highlights the importance of understanding the role of PU.1 in immunomodulatory effects and its potential as a therapeutic target in FL treatment.
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