期刊
CANCER IMMUNOLOGY RESEARCH
卷 7, 期 11, 页码 1876-1890出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2326-6066.CIR-18-0835
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资金
- Bloodwise Visiting Fellowship grant [14043]
- CRUK [A24721]
- South ampton CRUK Experimental Cancer Medicine Centre
- Koch Institute Support (core) Grant from the NCI [P30-CA14051]
- NIH [1R01NS104315, 1R35CA197605]
Therapy-resistant microenvironments represent a major barrier toward effective elimination of disseminated cancer. Many hematologic and solid tumors are resistant to therapeutic antibodies in the bone marrow (BM), but not in the periphery (e.g., spleen). We previously showed that cyclophosphamide (CTX) sensitizes the BM niche to antibody therapeutics. Here, we show that (i) BM resistance was induced not only by the tumor but also by the intrinsic BM microenvironment; (ii) CTX treatment overcame both intrinsic and extrinsic resistance mechanisms by augmenting macrophage activation and phagocytosis, including significant upregulation of activating Fc gamma receptors (Fc gamma RIII and Fc gamma RIV) and downregulation of the inhibitory receptor, Fc gamma RIIB; and (iii) CTX synergized with cetuximab (anti-EGFR) and trastuzumab (anti-Her2) in eliminating metastatic breast cancer in the BM of humanized mice. These findings provide insights into the mechanisms by which CTX synergizes with antibody therapeutics in resistant niche-specific organs and its applicability in treating BM-resident tumors.
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