Tumor control via targeting PD-L1 with chimeric antigen receptor modified NK cells.
Yvette RobbinsSarah GreeneJay FriedmanPaul E ClavijoCarter Van WaesKellsye P FabianMichelle R PadgetHoussein Abdul SaterJohn H LeePatrick Soon-ShiongJames L GulleyJeffrey SchlomJames W HodgeClint T AllenPublished in: eLife (2020)
Failed T cell-based immunotherapies in the presence of genomic alterations in antigen presentations pathways may be overcome by NK cell-based immunotherapy. This approach may still be limited by the presence of immunosuppressive myeloid populations. Here, we demonstrate that NK cells (haNKs) engineered to express a PD-L1 chimeric antigen receptor (CAR) haNKs killed a panel of human and murine head and neck cancer cells at low effector-to-target ratios in a PD-L1-dependent fashion. Treatment of syngeneic tumors resulted in CD8 and PD-L1-dependent tumor rejection or growth inhibition and a reduction in myeloid cells endogenously expressing high levels of PD-L1. Treatment of xenograft tumors resulted in PD-L1-dependent tumor growth inhibition. PD-L1 CAR haNKs reduced levels of macrophages and other myeloid cells endogenously expressing high PD-L1 in peripheral blood from patients with head and neck cancer. The clinical study of PD-L1 CAR haNKs is warranted.
Keyphrases
- nk cells
- induced apoptosis
- dendritic cells
- peripheral blood
- acute myeloid leukemia
- bone marrow
- cell cycle arrest
- endothelial cells
- clinical trial
- signaling pathway
- oxidative stress
- combination therapy
- endoplasmic reticulum stress
- dna methylation
- gene expression
- cancer therapy
- copy number
- induced pluripotent stem cells
- double blind