Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, California, USA.
Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California, USA.
J Immunother Cancer. 2021 Mar;9(3). doi: 10.1136/jitc-2020-002022.
Limited therapeutic options are available for triple-negative breast cancer (TNBC), emphasizing an urgent need for more effective treatment approaches. The development of strategies by targeting tumor-associated macrophages (TAMs) to stimulate their ability of Programmed Cell Removal (PrCR) provides a promising new immunotherapy for TNBC treatment.
CD47 is a critical self-protective "don't eat me" signal on multiple human cancers against macrophage immunosurveillance. Using human and mouse TNBC preclinical models, we evaluated the efficacy of PrCR-based immunotherapy by blocking CD47. We performed high-throughput screens on FDA-approved anti-cancer small molecule compounds for agents potentiating PrCR and enhancing the efficacy of CD47-targeted therapy for TNBC treatment.
We showed that CD47 was widely expressed on TNBC cells and TAMs represented the most abundant immune cell population in TNBC tumors. Blockade of CD47 enabled PrCR of TNBC cells, but the efficacy was not satisfactory. Our high-throughput screens identified cabazitaxel in enhancing PrCR-based immunotherapy. A combination of CD47 blockade and cabazitaxel treatment yielded a highly effective treatment strategy, promoting PrCR of TNBC cells and inhibiting tumor development and metastasis in preclinical models. We demonstrated that cabazitaxel potentiated PrCR by activating macrophages, independent of its cytotoxicity toward cancer cells. When treated with cabazitaxel, the molecular and phenotypic signatures of macrophages were polarized toward M1 state, and the NF-kB signaling pathway became activated.
The combination of CD47 blockade and macrophage activation by cabazitaxel synergizes to vastly enhance the elimination of TNBC cells. Our results show that targeting macrophages is a promising and effective strategy for TNBC treatment.
三阴性乳腺癌（TNBC）的治疗选择有限，这凸显了迫切需要更有效的治疗方法。通过靶向肿瘤相关巨噬细胞（TAMs）来刺激其程序性细胞清除（PrCR）能力的策略为 TNBC 的治疗提供了一种很有前途的新免疫疗法。
CD47 是多种人类癌症针对巨噬细胞免疫监视的关键自我保护“别吃我”信号。我们使用人类和小鼠 TNBC 临床前模型，通过阻断 CD47 来评估基于 PrCR 的免疫疗法的疗效。我们对 FDA 批准的抗癌小分子化合物进行了高通量筛选，以寻找增强 PrCR 并提高 CD47 靶向治疗 TNBC 疗效的药物。
我们表明，CD47 在 TNBC 细胞上广泛表达，TAMs 是 TNBC 肿瘤中最丰富的免疫细胞群体。阻断 CD47 可使 TNBC 细胞发生 PrCR，但疗效并不理想。我们的高通量筛选鉴定出卡巴他赛可增强基于 PrCR 的免疫疗法。CD47 阻断与卡巴他赛联合治疗产生了一种非常有效的治疗策略，可促进 TNBC 细胞的 PrCR，并抑制临床前模型中的肿瘤发展和转移。我们证明，卡巴他赛通过激活巨噬细胞增强 PrCR，而不依赖于其对癌细胞的细胞毒性。用卡巴他赛处理后，巨噬细胞的分子和表型特征向 M1 状态极化，NF-kB 信号通路被激活。
CD47 阻断与卡巴他赛激活巨噬细胞的联合作用可极大增强 TNBC 细胞的清除。我们的研究结果表明，靶向巨噬细胞是一种很有前途且有效的 TNBC 治疗策略。
