Tumor control via targeting PD-L1 with chimeric antigen receptor modified NK cells

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.

当抗原呈递通路（antigen presentation pathways）发生基因组改变时，基于T细胞的免疫疗法（T cell-based immunotherapy）往往会失效，此类难题可通过基于NK细胞的免疫疗法（NK cell-based immunotherapy）加以解决。不过该疗法仍可能受免疫抑制性髓系细胞群（immunosuppressive myeloid populations）的限制。本研究证实，经工程化改造以表达PD-L1嵌合抗原受体（PD-L1 chimeric antigen receptor, CAR）的NK细胞（haNKs），可在低效靶比（effector-to-target ratios）条件下以PD-L1依赖的方式，杀伤一组人类及小鼠头颈癌细胞系。对同基因肿瘤（syngeneic tumors）进行干预后，可实现CD8依赖及PD-L1依赖的肿瘤排斥或生长抑制，并可减少内源性高表达PD-L1的髓系细胞；对异种移植肿瘤（xenograft tumors）进行干预，则可实现PD-L1依赖的肿瘤生长抑制。PD-L1 CAR haNK细胞可降低头颈癌患者外周血中内源性高表达PD-L1的巨噬细胞及其他髓系细胞的水平。针对PD-L1 CAR haNK细胞的临床研究具备充分合理性，亟需开展。