University of Groningen, University Medical Center Groningen, Department of Hematology, Groningen, the Netherlands.
University of Groningen, University Medical Center Groningen, Department of Medical Oncology, Groningen, the Netherlands.
Cancer Immunol Res. 2019 Oct;7(10):1663-1671. doi: 10.1158/2326-6066.CIR-18-0781. Epub 2019 Aug 13.
Addition of rituximab (R) to "CHOP" (cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy improved outcome for diffuse large B-cell lymphoma (DLBCL) patients. Approximately 40% of patients who receive R-CHOP still succumb to disease due to intrinsic resistance or relapse. A potential negative regulator of DLBCL treatment outcome is the CD47 "don't eat me" immune checkpoint. To delineate the impact of CD47, we used a clinically and molecularly well-annotated cohort of 939 DLBCL patients, comprising both germinal center B-cell (GCB) and non-GCB DLBCL subtypes, treated with either CHOP or R-CHOP. High (above median) mRNA expression correlated with a detrimental effect on overall survival (OS) when DLBCL patients received R-CHOP therapy ( = 0.001), but not CHOP therapy ( = 0.645). Accordingly, patients with low expression benefited most from the addition of rituximab to CHOP [HR, 0.32; confidence interval (CI), 0.21-0.50; < 0.001]. This negative impact of high expression on OS after R-CHOP treatment was only evident in cancers of non-GCB origin (HR, 2.09; CI, 1.26-3.47; = 0.004) and not in the GCB subtype (HR, 1.16; CI, 0.68-1.99; = 0.58). This differential impact of in non-GCB and GCB was confirmed , as macrophage-mediated phagocytosis stimulated by rituximab was augmented by CD47-blocking antibody only in non-GCB cell lines. Thus, high expression of mRNA limited the benefit of addition of rituximab to CHOP in non-GCB patients, and CD47-blockade only augmented rituximab-mediated phagocytosis in non-GCB cell lines. Patients with non-GCB DLBCL may benefit from CD47-targeted therapy in addition to rituximab.
利妥昔单抗（R）联合“CHOP”（环磷酰胺、多柔比星、长春新碱和泼尼松）化疗改善了弥漫性大 B 细胞淋巴瘤（DLBCL）患者的预后。大约 40%接受 R-CHOP 治疗的患者仍因内在耐药或复发而死亡。CD47“别吃我”免疫检查点是 DLBCL 治疗结果的潜在负调节剂。为了描绘 CD47 的影响，我们使用了一个临床和分子上充分注释的 939 例 DLBCL 患者队列，包括生发中心 B 细胞（GCB）和非 GCB DLBCL 亚型，这些患者接受了 CHOP 或 R-CHOP 治疗。当 DLBCL 患者接受 R-CHOP 治疗时，高（高于中位数）mRNA 表达与总生存期（OS）的不良影响相关（=0.001），但与 CHOP 治疗无关（=0.645）。因此，低表达的患者从 CHOP 中添加利妥昔单抗获益最大[HR，0.32；置信区间（CI），0.21-0.50；<0.001]。R-CHOP 治疗后高表达对 OS 的负面影响仅在非 GCB 起源的癌症中明显（HR，2.09；CI，1.26-3.47；=0.004），而在 GCB 亚型中不明显（HR，1.16；CI，0.68-1.99；=0.58）。非 GCB 和 GCB 中 的这种差异影响得到了证实，因为只有在用 CD47 阻断抗体阻断 CD47 后，利妥昔单抗刺激的巨噬细胞吞噬作用才会增强。因此，在非 GCB 患者中，高表达 的 mRNA 限制了 CHOP 中添加利妥昔单抗的获益，而 CD47 阻断仅增强了非 GCB 细胞系中利妥昔单抗介导的吞噬作用。非 GCB DLBCL 患者可能从 CD47 靶向治疗联合利妥昔单抗中获益。
