PDF(Pubmed)
Abstract：
Rituximab (RTX) plus chemotherapy (R-CHOP) applied as a first-line therapy for lymphoma leads to a relapse in approximately 40% of the patients. Therefore, novel approaches to treat aggressive lymphomas are being intensively investigated. Several RTX-resistant (RR) cell lines have been established as surrogate models to study resistance to R-CHOP. Our study reveals that RR cells are characterized by a major downregulation of CD37, a molecule currently explored as a target for immunotherapy. Using CD20 knockout (KO) cell lines, we demonstrate that CD20 and CD37 form a complex, and hypothesize that the presence of CD20 stabilizes CD37 in the cell membrane. Consequently, we observe a diminished cytotoxicity of anti-CD37 monoclonal antibody (mAb) in complement-dependent cytotoxicity in both RR and CD20 KO cells that can be partially restored upon lysosome inhibition. On the other hand, the internalization rate of anti-CD37 mAb in CD20 KO cells is increased when compared to controls, suggesting unhampered efficacy of antibody drug conjugates (ADCs). Importantly, even a major downregulation in CD37 levels does not hamper the efficacy of CD37-directed chimeric antigen receptor (CAR) T cells. In summary, we present here a novel mechanism of CD37 regulation with further implications for the use of anti-CD37 immunotherapies.
摘要：
利妥昔单抗（RTX）加化疗（R-CHOP）作为淋巴瘤的一线治疗导致约40％的患者复发。因此,目前正在深入研究治疗侵袭性淋巴瘤的新方法.已经建立了几种RTX抗性(RR)细胞系作为替代模型来研究对R-CHOP的抗性。我们的研究表明，RR细胞的特征是CD37的主要下调，CD37是目前作为免疫疗法靶标的分子。使用CD20敲除（KO）细胞系，我们证明CD20和CD37形成复合物，并假设CD20的存在使细胞膜中的CD37稳定。因此,我们观察到,在RR和CD20KO细胞中,抗CD37单克隆抗体(mAb)的补体依赖性细胞毒性均减弱,在溶酶体抑制后可部分恢复.另一方面,与对照相比，抗CD37单克隆抗体在CD20KO细胞中的内在化率增加，提示抗体药物缀合物（ADC）的无阻碍疗效。重要的是,即使是CD37水平的大幅下调也不会妨碍CD37定向嵌合抗原受体(CAR)T细胞的功效.总之,我们在此提出了一种新的CD37调节机制,这对使用抗CD37免疫疗法具有进一步的意义.
