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Effect of cabazitaxel on macrophages improves CD47-targeted immunotherapy for triple-negative breast cancer.

肿瘤科 乳腺癌 癌症 免疫检查点 免疫系统 内科学 癌症免疫疗法 黑色素瘤 前列腺癌
作者
Xu Cao,Bolei Li,Jing Chen,Jessica Dang,Siqi Chen,E Gulsen Gunes,Bo Xu,Lei Tian,Sabina A Muend,Mustafa Raoof,Christiane Querfeld,Jianhua Yu,Steven T. Rosen,Yingyu Wang,Mingye Feng
出处
期刊:Journal for ImmunoTherapy of Cancer [BMJ]
卷期号:9 (3) 被引量:3
标识
DOI:10.1136/jitc-2020-002022
摘要

Background 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. Methods 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. Results 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. Conclusion 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.
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