Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.
Department of Immunology and Theranostics, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.
Sci Adv. 2022 Mar 18;8(11):eabl9171. doi: 10.1126/sciadv.abl9171.
Macrophages are essential in eliciting antibody-dependent cellular phagocytosis (ADCP) of cancer cells. However, a satisfactory anticancer efficacy of ADCP is contingent on early antibody administration, and resistance develops along with cancer progression. Here, we investigate the mechanisms underlying ADCP and demonstrate an effective combinatorial strategy to potentiate its efficacy. We identified paclitaxel as a universal adjuvant that efficiently potentiated ADCP by a variety of anticancer antibodies in multiple cancers. Rather than eliciting cytotoxicity on cancer cells, paclitaxel polarized macrophages toward a state with enhanced phagocytic ability. Paclitaxel-treated macrophages down-regulated cell surface CSF1R whose expression was negatively correlated with patient survival in multiple malignancies. The suppression of CSF1R in macrophages enhanced ADCP of cancer cells, suggesting a role of CSF1R in regulating macrophage phagocytic ability. Together, these findings define a potent strategy for using conventional anticancer drugs to stimulate macrophage phagocytosis and promote the therapeutic efficacy of clinical anticancer antibodies.
巨噬细胞在引发癌细胞抗体依赖的细胞吞噬作用（ADCP）中起关键作用。然而，ADCP 的令人满意的抗癌疗效取决于早期抗体的给药，并且随着癌症的进展，会产生耐药性。在这里，我们研究了 ADCP 的机制，并展示了一种有效的联合策略来增强其疗效。我们发现紫杉醇是一种通用佐剂，它可以通过多种抗癌抗体在多种癌症中有效地增强 ADCP。紫杉醇并没有在癌细胞上引起细胞毒性，而是将巨噬细胞极化到一种具有增强吞噬能力的状态。紫杉醇处理的巨噬细胞下调了细胞表面 CSF1R 的表达，其表达与多种恶性肿瘤患者的生存呈负相关。巨噬细胞中 CSF1R 的抑制增强了癌细胞的 ADCP，表明 CSF1R 在调节巨噬细胞吞噬能力方面起作用。总之，这些发现定义了一种使用传统抗癌药物刺激巨噬细胞吞噬作用并提高临床抗癌抗体治疗效果的有效策略。
