Cyclophosphamide-Mediated Induction of Myeloid-Derived Suppressor Cells In Vivo: Kinetics of Accumulation, Immune Profile, and Immunomodulation by Oleanane-Type Triterpenoids

TL;DR

This study shows that cyclophosphamide in chemotherapy increases immune-suppressing cells, and some triterpenoids can either reduce or worsen this effect.

Contribution

The study reveals the structure-dependent immunomodulatory effects of triterpenoids on chemotherapy-induced MDSCs.

Findings

Cyclophosphamide is the main driver of MDSC accumulation in the CHOP regimen.

Glycyrrhizic acid reduces MDSCs and restores T-cell function, while febroxolone methyl worsens immunosuppression.

FM promotes MDSC expansion and enhances their immunosuppressive function in vivo and in vitro.

Abstract

Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells that strongly suppress immunity and expand during tumor progression. Various antitumor chemotherapy agents can induce MDSC accumulation, reducing treatment effectiveness. We investigated the impact of the CHOP regimen and its components (cyclophosphamide (CTX), doxorubicin, vincristine, and prednisolone) on the dynamics of MDSC accumulation and the associated changes in immune cell profiles in the peripheral blood and spleen of healthy and lymphosarcoma RLS40-bearing CBA mice. CHOP induced significant thymic atrophy and splenomegaly, T-cell depletion, and robust accumulation of MDSCs, primarily polymorphonuclear MDSCs. Kinetic analysis in healthy mice revealed splenic MDSC expansion and T-cell depletion peaked 10-day post-CHOP, driven mainly by CTX; whereas doxorubicin, vincristine, and prednisolone exerted minimal immunological effects. To mitigate CTX-induced MDSCs, glycyrrhizic acid (GLZ), a natural triterpenoid with known immunomodulatory properties, and febroxolone methyl (FM), its novel cyano enone derivative, were administered to CTX-treated mice. GLZ significantly attenuated splenic MDSC accumulation, partially restored T-cell function, and improved immune organ morphology. Conversely, FM exacerbated immunosuppression by expanding MDSCs, enhancing their function by upregulation of Nos1 and Ido1 in vivo, and promoting the generation of highly immunosuppressive bone marrow-derived MDSCs in vitro. Thus, our results highlight CTX’s central role in CHOP-induced MDSC expansion. The structure-dependent duality of triterpenoids, countering (GLZ) or promoting (FM) MDSC expansion, offers therapeutic potential for pathologies ranging from chemotherapy-induced side effects to autoimmunity.

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