Abstract：
CD47 expressed on cancer cells enables macrophage immune evasion. Blocking CD47 using anti-CD47 monoclonal antibodies (mAbs) is a promising strategy. The anti-CD47 mAb TJC4 has anti-tumor activity but lacks hematological toxicity. Venetoclax, a B-cell lymphoma 2 (BCL-2) inhibitor for B-cell malignancy, induces phosphatidylserine (PS) extracellular exposure, representing an \"eat-me\" signal for macrophages. The present study aimed to explore whether TJC4-Venetoclax combined therapy exerts synergistic anti-cancer properties in B-cell lymphoma. In vitro, flow cytometry and microscopy assessed whether TJC4 monotherapy or combination treatment could promote macrophage-mediated phagocytosis of tumor cells. Induced PS exposure on the cell membrane was measured using flow cytometry with Annexin V-FITC staining. In vivo, Venetoclax and TJC4\'s synergistic anti-tumor effects were evaluated. B cell lymphoma cell lines express high levels of CD47 and patients with diffuse large B cell lymphoma expressing CD47 have a worse clinical prognosis. TJC4 eliminates tumor cells via macrophage-mediated phagocytosis. In vitro and in vivo, the TJC4-Venetoclax combination increased phagocytosis significantly compared with either agent alone, showing synergistic phagocytosis, and displayed synergistic anti-cancer properties in B-cell lymphoma. Our results support the TJC4-Venetoclax combination as a promising therapy, and suppressing BCL-2 and CD47 simultaneously could represent a novel therapeutic paradigm for B-cell lymphoma.
摘要：
在癌细胞上表达的CD47使巨噬细胞免疫逃避。使用抗CD47单克隆抗体(mAb)阻断CD47是一种有前途的策略。抗CD47mAbTJC4具有抗肿瘤活性,但缺乏血液学毒性。维奈托克,B细胞恶性肿瘤的B细胞淋巴瘤2（BCL-2）抑制剂，诱导磷脂酰丝氨酸（PS）细胞外暴露，代表巨噬细胞的“吃我”信号。本研究旨在探讨TJC4-维奈托克联合治疗是否在B细胞淋巴瘤中发挥协同抗癌作用。体外，流式细胞术和显微镜检查评估TJC4单药治疗或联合治疗是否可以促进巨噬细胞介导的肿瘤细胞吞噬作用.使用具有膜联蛋白V-FITC染色的流式细胞术测量细胞膜上的诱导PS暴露。在体内,评价维奈托克和TJC4的协同抗肿瘤作用。B细胞淋巴瘤细胞系表达高水平的CD47，表达CD47的弥漫性大B细胞淋巴瘤患者的临床预后较差。TJC4通过巨噬细胞介导的吞噬作用消除肿瘤细胞。在体外和体内，TJC4-维奈托克联合用药与任一单独用药相比显著增加吞噬作用,显示协同吞噬作用，并在B细胞淋巴瘤中显示出协同抗癌特性。我们的结果支持TJC4-Venetoclax组合作为一种有前途的治疗方法，同时抑制BCL-2和CD47可以代表B细胞淋巴瘤的新治疗模式。
