Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.
Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
J Immunother Cancer. 2023 Sep;11(9). doi: 10.1136/jitc-2023-007386.
Enzalutamide, a next-generation antiandrogen agent, is approved for the treatment of metastatic castration-resistant prostate cancer (CRPC). While enzalutamide has been shown to improve time to progression and extend overall survival in men with CRPC, the majority of patients ultimately develop resistance to treatment. Immunotherapy approaches have shown limited clinical benefit in this patient population; understanding resistance mechanisms could help develop novel and more effective treatments for CRPC. One of the mechanisms involved in tumor resistance to various therapeutics is tumor phenotypic plasticity, whereby carcinoma cells acquire mesenchymal features with or without the loss of classical epithelial characteristics. This work investigated a potential link between enzalutamide resistance, tumor phenotypic plasticity, and resistance to immune-mediated lysis in prostate cancer.
Models of prostate cancer resistant to enzalutamide were established by long-term exposure of human prostate cancer cell lines to the drug in culture. Tumor cells were evaluated for phenotypic features in vitro and in vivo, as well as for sensitivity to immune effector cell-mediated cytotoxicity.
Resistance to enzalutamide was associated with gain of mesenchymal tumor features, upregulation of estrogen receptor expression, and significantly reduced tumor susceptibility to natural killer (NK)-mediated lysis, an effect that was associated with decreased tumor/NK cell conjugate formation with enzalutamide-resistant cells. Fulvestrant, a selective estrogen receptor degrader, restored the formation of target/NK cell conjugates and increased susceptibility to NK cell lysis in vitro. In vivo, fulvestrant demonstrated antitumor activity against enzalutamide-resistant cells, an effect that was associated with activation of NK cells.
NK cells are emerging as a promising therapeutic approach in prostate cancer. Modifying tumor plasticity via blockade of estrogen receptor with fulvestrant may offer an opportunity for immune intervention via NK cell-based approaches in enzalutamide-resistant CRPC.
恩扎卢胺是一种新一代的抗雄激素药物，被批准用于治疗转移性去势抵抗性前列腺癌（CRPC）。虽然恩扎卢胺已被证明可改善 CRPC 患者的无进展生存期并延长总生存期，但大多数患者最终会对治疗产生耐药性。免疫疗法在这一患者群体中的临床获益有限；了解耐药机制有助于开发治疗 CRPC 的新型、更有效的方法。肿瘤对各种治疗方法产生耐药性的机制之一是肿瘤表型可塑性，即癌细胞获得间充质特征，无论是否丧失经典上皮特征。这项工作研究了恩扎卢胺耐药性、肿瘤表型可塑性和前列腺癌对免疫介导的裂解耐药性之间的潜在联系。
通过在培养物中长期暴露于药物来建立对恩扎卢胺耐药的前列腺癌细胞系模型。在体外和体内评估肿瘤细胞的表型特征，以及对免疫效应细胞介导的细胞毒性的敏感性。
对恩扎卢胺的耐药性与获得间充质肿瘤特征、雌激素受体表达上调以及肿瘤对自然杀伤（NK）介导的裂解的敏感性显著降低有关，这种效应与恩扎卢胺耐药细胞中肿瘤/NK 细胞缀合物的形成减少有关。选择性雌激素受体降解剂氟维司群恢复了靶/NK 细胞缀合物的形成，并增加了恩扎卢胺耐药细胞在体外对 NK 细胞裂解的敏感性。在体内，氟维司群对恩扎卢胺耐药细胞表现出抗肿瘤活性，这与 NK 细胞的激活有关。
NK 细胞作为一种有前途的前列腺癌治疗方法正在出现。通过氟维司群阻断雌激素受体来改变肿瘤可塑性，可能为基于 NK 细胞的方法提供免疫干预的机会，用于治疗恩扎卢胺耐药的 CRPC。
