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Cyclophosphamide enhances cancer antibody immunotherapy in the resistant bone marrow niche by modulating macrophage FcγR expression

Cyclophosphamide enhances cancer antibody immunotherapy in the resistant bone marrow niche by modulating macrophage FcγR expression
Cyclophosphamide enhances cancer antibody immunotherapy in the resistant bone marrow niche by modulating macrophage FcγR expression
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.
2326-6066
1876-1890
Roghanian, Ali
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Hu, Guangan
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Fraser, Christopher
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Singh, Maneesh
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Foxall, Russell
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Meyer, Matthew J.
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Lees, Emma
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Huet, Heather
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Glennie, Martin
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Beers, Stephen
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Lim, Sean
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Ashton-Key, Margaret
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Thirdborough, Stephen
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Cragg, Mark
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Chen, Jianzhu
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Roghanian, Ali
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Hu, Guangan
a180f467-f206-4878-b094-60ecacc834c7
Fraser, Christopher
c6722402-4c3a-4156-93ce-a51a3388ffa8
Singh, Maneesh
99c21be7-e456-45dc-a71a-e92828959486
Foxall, Russell
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Meyer, Matthew J.
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Lees, Emma
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Huet, Heather
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Glennie, Martin
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Beers, Stephen
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Lim, Sean
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Ashton-Key, Margaret
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Thirdborough, Stephen
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Cragg, Mark
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Chen, Jianzhu
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Roghanian, Ali, Hu, Guangan, Fraser, Christopher, Singh, Maneesh, Foxall, Russell, Meyer, Matthew J., Lees, Emma, Huet, Heather, Glennie, Martin, Beers, Stephen, Lim, Sean, Ashton-Key, Margaret, Thirdborough, Stephen, Cragg, Mark and Chen, Jianzhu (2019) Cyclophosphamide enhances cancer antibody immunotherapy in the resistant bone marrow niche by modulating macrophage FcγR expression. Cancer Immunology Research, 7 (11), 1876-1890. (doi:10.1158/2326-6066.CIR-18-0835).

Record type: Article

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.

Text
Roghanian CIR-18-0835R Merged (06May2019) - Accepted Manuscript
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Accepted/In Press date: 21 August 2019
e-pub ahead of print date: 26 August 2019
Published date: November 2019

Identifiers

Local EPrints ID: 434735
URI: http://eprints.soton.ac.uk/id/eprint/434735
ISSN: 2326-6066
PURE UUID: e1a7eeac-f257-4ebd-adf4-88e21722f0f8
ORCID for Ali Roghanian: ORCID iD orcid.org/0000-0003-1316-4218
ORCID for Stephen Beers: ORCID iD orcid.org/0000-0002-3765-3342
ORCID for Mark Cragg: ORCID iD orcid.org/0000-0003-2077-089X

Catalogue record

Date deposited: 08 Oct 2019 16:30
Last modified: 26 Nov 2021 07:13

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Contributors

Author: Ali Roghanian ORCID iD
Author: Guangan Hu
Author: Christopher Fraser
Author: Maneesh Singh
Author: Russell Foxall
Author: Matthew J. Meyer
Author: Emma Lees
Author: Heather Huet
Author: Martin Glennie
Author: Stephen Beers ORCID iD
Author: Sean Lim
Author: Margaret Ashton-Key
Author: Mark Cragg ORCID iD
Author: Jianzhu Chen

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