Cyclophosphamide depletes tumor infiltrating T regulatory cells and combined with anti-PD-1 therapy improves survival in murine neuroblastoma

• Published in: iScience Vol. 25; no. 9; p. 104995
• Main Authors: Webb, Emily R., Moreno-Vicente, Julia, Easton, Alistair, Lanati, Silvia, Taylor, Martin, James, Sonya, Williams, Emily L., English, Vikki, Penfold, Chris, Beers, Stephen A., Gray, Juliet C.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 16-09-2022; Elsevier
• Subjects: Biological sciences; Cancer; Immunology; Microenvironment; Biological sciences; Immunology; Microenvironment; Cancer
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2022.104995

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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•Low dose cyclophosphamide selectively depletes tumor Tregs in neuroblastoma models•Depletion of tumor Tregs is transient and dependent on apoptosis•Cyclophosphamide and anti-PD-1 mAb are an effective combinational therapy•Metronomic cyclophosphamide is more effective than a single dose in resistant tumors
Microenvironment; Biological sciences; Immunology; Cancer