Patients with otherwise treatment-resistant Hodgkin lymphoma could benefit from chimeric antigen receptor T-cell (CART) therapy. However, Hodgkin lymphoma lacks CD19 and contains a highly immunosuppressive tumor microenvironment (TME). We hypothesized that in Hodgkin lymphoma, CART should target both malignant cells and the TME. We demonstrated CD123 on both Hodgkin lymphoma cells and TME, including tumor-associated macrophages (TAM). In vitro, Hodgkin lymphoma cells convert macrophages toward immunosuppressive TAMs that inhibit T-cell proliferation. In contrast, anti-CD123 CART recognized and killed TAMs, thus overcoming immunosuppression. Finally, we showed in immunodeficient mouse models that CART123 eradicated Hodgkin lymphoma and established long-term immune memory. A novel platform that targets malignant cells and the microenvironment may be needed to successfully treat malignancies with an immunosuppressive milieu.

SIGNIFICANCE: Anti-CD123 chimeric antigen receptor T cells target both the malignant cells and TAMs in Hodgkin lymphoma, thereby eliminating an important immunosuppressive component of the tumor microenvironment. Cancer Discov; 7(10); 1–14. ©2017 AACR.

患有其他治疗耐药的霍奇金淋巴瘤患者可以从嵌合抗原受体 T 细胞 (CART) 治疗中受益。然而，霍奇金淋巴瘤缺乏 CD19，并含有高度免疫抑制的肿瘤微环境 (TME)。我们假设，在霍奇金淋巴瘤中，CART 应同时针对恶性细胞和 TME。我们在霍奇金淋巴瘤细胞和 TME（包括肿瘤相关巨噬细胞 (TAM)）上证明了 CD123。在体外，霍奇金淋巴瘤细胞将巨噬细胞转化为抑制 T 细胞增殖的免疫抑制 TAM。相比之下，抗 CD123 CART 可识别并杀死 TAM，从而克服免疫抑制。最后，我们在免疫缺陷小鼠模型中证明，CART123 根除霍奇金淋巴瘤并建立长期免疫记忆。可能需要一个针对恶性细胞和微环境的新平台来成功治疗具有免疫抑制环境的恶性肿瘤。

意义：抗 CD123 嵌合抗原受体 T 细胞靶向霍奇金淋巴瘤中的恶性细胞和 TAM，从而消除肿瘤微环境中重要的免疫抑制成分。癌症发现；7(10)；1-14。©2017 AACR。