The University of Southampton
University of Southampton Institutional Repository

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
e2b032c2-60a0-4522-a3d8-56a768792f36
Hu, Guangan
a180f467-f206-4878-b094-60ecacc834c7
Fraser, Christopher
c6722402-4c3a-4156-93ce-a51a3388ffa8
Singh, Maneesh
99c21be7-e456-45dc-a71a-e92828959486
Foxall, Russell
cfe3a818-a281-4bcb-8889-e1d0b591117c
Meyer, Matthew J.
aff7f6d8-a54e-4f9f-bad4-ae753371bb45
Lees, Emma
cdd6d29d-1e01-43d1-9925-cc2540384137
Huet, Heather
5190811c-d40d-47a9-899c-ab02b365b449
Glennie, Martin
9f6f0eff-4560-48c2-80cd-0ec116110ded
Beers, Stephen
a02548be-3ffd-41ab-9db8-d6e8c3b499a2
Lim, Sean
1afe5aa1-61a4-4a7b-927f-5e671f885196
Ashton-Key, Margaret
5111ac18-7d4f-4ef0-9c71-0a44c37aaed4
Thirdborough, Stephen
161784fb-c8e3-4beb-86b1-cd8bc8ddf8de
Cragg, Mark
ec97f80e-f3c8-49b7-a960-20dff648b78c
Chen, Jianzhu
3cdf9960-ff91-4cad-8b71-2b0dafe11c4d
Roghanian, Ali
e2b032c2-60a0-4522-a3d8-56a768792f36
Hu, Guangan
a180f467-f206-4878-b094-60ecacc834c7
Fraser, Christopher
c6722402-4c3a-4156-93ce-a51a3388ffa8
Singh, Maneesh
99c21be7-e456-45dc-a71a-e92828959486
Foxall, Russell
cfe3a818-a281-4bcb-8889-e1d0b591117c
Meyer, Matthew J.
aff7f6d8-a54e-4f9f-bad4-ae753371bb45
Lees, Emma
cdd6d29d-1e01-43d1-9925-cc2540384137
Huet, Heather
5190811c-d40d-47a9-899c-ab02b365b449
Glennie, Martin
9f6f0eff-4560-48c2-80cd-0ec116110ded
Beers, Stephen
a02548be-3ffd-41ab-9db8-d6e8c3b499a2
Lim, Sean
1afe5aa1-61a4-4a7b-927f-5e671f885196
Ashton-Key, Margaret
5111ac18-7d4f-4ef0-9c71-0a44c37aaed4
Thirdborough, Stephen
161784fb-c8e3-4beb-86b1-cd8bc8ddf8de
Cragg, Mark
ec97f80e-f3c8-49b7-a960-20dff648b78c
Chen, Jianzhu
3cdf9960-ff91-4cad-8b71-2b0dafe11c4d

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
Download (16MB)

More information

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: 17 Mar 2024 03:18

Export record

Altmetrics

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

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of http://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×