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Cyclophosphamide Enhances Cancer Antibody Immunotherapy in the Resistant Bone Marrow Niche by Modulating Macrophage FcγR Expression.
- Source :
-
Cancer immunology research [Cancer Immunol Res] 2019 Nov; Vol. 7 (11), pp. 1876-1890. Date of Electronic Publication: 2019 Aug 26. - Publication Year :
- 2019
-
Abstract
- 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 Fcγ receptors (FcγRIII and FcγRIV) and downregulation of the inhibitory receptor, FcγRIIB; 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.<br /> (©2019 American Association for Cancer Research.)
- Subjects :
- Animals
Antineoplastic Agents, Immunological immunology
Antineoplastic Agents, Immunological therapeutic use
Bone Marrow drug effects
Bone Marrow pathology
Cyclophosphamide immunology
Cyclophosphamide therapeutic use
Drug Resistance, Neoplasm immunology
Gene Expression Regulation drug effects
Humans
Immunotherapy
Macrophage Activation drug effects
Macrophages immunology
Macrophages metabolism
Mice
Neoplasms, Experimental immunology
Neoplasms, Experimental therapy
Receptors, IgG metabolism
Tumor Microenvironment drug effects
Tumor Microenvironment immunology
Antineoplastic Agents, Immunological pharmacology
Bone Marrow immunology
Cyclophosphamide pharmacology
Drug Resistance, Neoplasm drug effects
Macrophages drug effects
Receptors, IgG genetics
Subjects
Details
- Language :
- English
- ISSN :
- 2326-6074
- Volume :
- 7
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Cancer immunology research
- Publication Type :
- Academic Journal
- Accession number :
- 31451483
- Full Text :
- https://doi.org/10.1158/2326-6066.CIR-18-0835