Department of Medical Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY 14203, USA.
Aging (Albany NY). 2020 Dec 3;13(1):181-193. doi: 10.18632/aging.202180.
Intercellular adhesion molecule-1 (ICAM-1) is a cell-surface receptor contributing to lymphocyte homing, adhesion and activation. The prognostic significance of the protein is unknown in diffuse large B-cell lymphoma (DLBCL) in post-rituximab era. We detected expression of ICAM-1 immunohistochemically in 102 DLBCL tissue samples. Overexpression of ICAM-1 was found in 28 (27.5%) cases. In patients with low ICAM-1 expression levels, the addition of rituximab to CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) chemotherapy resulted in an improved overall response rate, progression-free survival (PFS) and overall survival (OS) (=0.019, 0.01, 0.02). In pre-clinical models, we found that chronic exposure of cell lines to rituximab led to downregulation of ICAM-1 and acquirement of a rituximab resistant phenotype. In vitro exposure of rituximab resulted in rapid aggregation of B-cells regardless of the ICAM-1 expression levels. MTT assay showed knockdown of ICAM-1 could cause rituximab resistance. Neutralization of ICAM-1 did not affect rituximab activity in vitro and in vivo. Our data illustrated that in post-rituximab era, R-CHOP significantly improved the ORR, PFS and OS in ICAM-1 negative subset patients. Downregulation of ICAM-1 may contribute to rituximab resistance, and that rituximab, by promoting cell-cell aggregation, may sensitize cells to the cytotoxic effects of chemotherapy agents.
细胞间黏附分子-1（ICAM-1）是一种细胞表面受体，有助于淋巴细胞归巢、黏附和激活。在利妥昔单抗时代，ICAM-1 蛋白在弥漫性大 B 细胞淋巴瘤（DLBCL）中的预后意义尚不清楚。我们用免疫组化方法检测了 102 例 DLBCL 组织样本中 ICAM-1 的表达。发现 28 例（27.5%）存在 ICAM-1 过表达。在 ICAM-1 低表达的患者中，利妥昔单抗联合 CHOP（环磷酰胺、多柔比星、长春新碱和泼尼松）化疗可提高总缓解率、无进展生存期（PFS）和总生存期（OS）（=0.019，0.01，0.02）。在临床前模型中，我们发现细胞系长期暴露于利妥昔单抗会导致 ICAM-1 下调，并获得利妥昔单抗耐药表型。无论 ICAM-1 表达水平如何，利妥昔单抗体外暴露都会导致 B 细胞迅速聚集。MTT 检测表明，ICAM-1 敲低可导致利妥昔单抗耐药。中和 ICAM-1 不影响利妥昔单抗在体外和体内的活性。我们的数据表明，在利妥昔单抗时代，R-CHOP 可显著提高 ICAM-1 阴性亚组患者的 ORR、PFS 和 OS。ICAM-1 的下调可能导致利妥昔单抗耐药，而利妥昔单抗通过促进细胞间聚集，可能使细胞对化疗药物的细胞毒性作用更加敏感。
