Cyclophosphamide depletes tumor infiltrating T regulatory cells and combined with anti-PD-1 therapy improves survival in murine neuroblastoma
Cyclophosphamide depletes tumor infiltrating T regulatory cells and combined with anti-PD-1 therapy improves survival in murine neuroblastoma
The outcome for children with high-risk neuroblastoma is poor despite intensive multi-modal treatment protocols. Toxicity from current treatments is significant, and novel approaches are needed to improve outcome. Cyclophosphamide (CPM) is a key component of current chemotherapy regimens and is known to have immunomodulatory effects. However, this has not been investigated in the context of tumor infiltrating lymphocytes in neuroblastoma. Using murine models of neuroblastoma, the immunomodulatory effects of low-dose CPM were investigated using detailed immunophenotyping. We demonstrated that CPM resulted in a specific depletion of intratumoral T regulatory cells by apoptosis, and when combined with anti-PD-1 antibody therapy, this resulted in improved therapeutic efficacy. CPM combined with anti-PD-1 therapy was demonstrated to be an effective combinational therapy, with metronomic CPM found to be more effective than single dosing in more resistant tumor models. Overall, this pre-clinical data strongly support clinical evaluation of such combination strategies in neuroblastoma.
Biological sciences, Cancer, Immunology, Microenvironment
Webb, Emily Rose
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Moreno Vicente, Julia
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Easton, Alistair
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Lanati, Silvia
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Taylor, Martin
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James, Sonya
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Williams, Emily L.
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Penfold, Christine
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Beers, Stephen
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Gray, Juliet
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English, Vikki
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16 September 2022
Webb, Emily Rose
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Moreno Vicente, Julia
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Easton, Alistair
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Lanati, Silvia
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Taylor, Martin
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James, Sonya
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Williams, Emily L.
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Penfold, Christine
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Beers, Stephen
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Gray, Juliet
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English, Vikki
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Webb, Emily Rose, Moreno Vicente, Julia, Easton, Alistair, Lanati, Silvia, Taylor, Martin, James, Sonya, Williams, Emily L., Penfold, Christine, Beers, Stephen, Gray, Juliet and English, Vikki
(2022)
Cyclophosphamide depletes tumor infiltrating T regulatory cells and combined with anti-PD-1 therapy improves survival in murine neuroblastoma.
iScience, 25 (9), [104995].
(doi:10.1016/j.isci.2022.104995).
Abstract
The outcome for children with high-risk neuroblastoma is poor despite intensive multi-modal treatment protocols. Toxicity from current treatments is significant, and novel approaches are needed to improve outcome. Cyclophosphamide (CPM) is a key component of current chemotherapy regimens and is known to have immunomodulatory effects. However, this has not been investigated in the context of tumor infiltrating lymphocytes in neuroblastoma. Using murine models of neuroblastoma, the immunomodulatory effects of low-dose CPM were investigated using detailed immunophenotyping. We demonstrated that CPM resulted in a specific depletion of intratumoral T regulatory cells by apoptosis, and when combined with anti-PD-1 antibody therapy, this resulted in improved therapeutic efficacy. CPM combined with anti-PD-1 therapy was demonstrated to be an effective combinational therapy, with metronomic CPM found to be more effective than single dosing in more resistant tumor models. Overall, this pre-clinical data strongly support clinical evaluation of such combination strategies in neuroblastoma.
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FINAL Webb et al; iScience
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Published date: 16 September 2022
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© 2022 The Author(s).
Keywords:
Biological sciences, Cancer, Immunology, Microenvironment
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Local EPrints ID: 470424
URI: http://eprints.soton.ac.uk/id/eprint/470424
ISSN: 2589-0042
PURE UUID: 0c421add-e23d-4dd6-9b59-9aa287d9985b
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Date deposited: 10 Oct 2022 16:59
Last modified: 17 Mar 2024 07:31
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Author:
Emily Rose Webb
Author:
Julia Moreno Vicente
Author:
Alistair Easton
Author:
Martin Taylor
Author:
Sonya James
Author:
Emily L. Williams
Author:
Christine Penfold
Author:
Vikki English
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