Inhibiting the biogenesis of myeloid-derived suppressor cells enhances immunotherapy efficacy against mammary tumor progression
Sean H. Colligan, … , Michael J. Nemeth, Scott I. Abrams
Sean H. Colligan, … , Michael J. Nemeth, Scott I. Abrams
Published December 1, 2022
Citation Information: J Clin Invest. 2022;132(23):e158661. https://doi.org/10.1172/JCI158661.
View: Text | PDF
Research Article Immunology

Inhibiting the biogenesis of myeloid-derived suppressor cells enhances immunotherapy efficacy against mammary tumor progression

Abstract

While immune checkpoint inhibitors (ICIs) have transformed the therapeutic landscape in oncology, they are effective in select subsets of patients. Efficacy may be limited by tumor-driven immune suppression, of which 1 key mechanism is the development of myeloid-derived suppressor cells (MDSCs). A fundamental gap in MDSC therapeutics is the lack of approaches that target MDSC biogenesis. We hypothesized that targeting MDSC biogenesis would mitigate MDSC burden and bolster tumor responses to ICIs. We tested a class of agents, dihydroorotate dehydrogenase (DHODH) inhibitors, that have been previously shown to restore the terminal differentiation of leukemic myeloid progenitors. DHODH inhibitors have demonstrated preclinical safety and are under clinical study for hematologic malignancies. Using mouse models of mammary cancer that elicit robust MDSC responses, we demonstrated that the DHODH inhibitor brequinar (a) suppressed MDSC production from early-stage myeloid progenitors, which was accompanied by enhanced myeloid maturation; (b) augmented the antitumor and antimetastatic activities of programmed cell death 1–based (PD-1–based) ICI therapy in ICI-resistant mammary cancer models; and (c) acted in concert with PD-1 blockade through modulation of MDSC and CD8+ T cell responses. Moreover, brequinar facilitated myeloid maturation and inhibited immune-suppressive features in human bone marrow culture systems. These findings advance the concept of MDSC differentiation therapy in immuno-oncology.

Authors

Sean H. Colligan, Andrea M. Amitrano, Robert A. Zollo, Jennifer Peresie, Elliot D. Kramer, Brian Morreale, Joseph Barbi, Prashant K. Singh, Han Yu, Jianmin Wang, Mateusz Opyrchal, David B. Sykes, Michael J. Nemeth, Scott I. Abrams

×

Figure 8

BRQ inhibits the development of an immunosuppressive phenotype in human myeloid cells.

Options: View larger image (or click on image) Download as PowerPoint
BRQ inhibits the development of an immunosuppressive phenotype in human ...
Human BM cells were cultured for 96 hours with recombinant human GM-CSF (rhGM-CSF) and rhG-CSF (40 ng/mL each) plus 1 μM BRQ (from Clear Creek) or vehicle. (A) Flow cytometric analysis of CD33 expression and SSC properties (84%–88% CD33+ with or without BRQ treatment). FSC-A, forward scatter area; FSC-H, forward scatter height. (B) Percentage of CD33+ myeloid cells exhibiting high SSC (SSChi). (C) Histograms depicting CD101, CD11b, or HLA-DR expression by the gated CD33+ cells and quantification of the MFI values for CD101, CD11b, and HLA-DR by the gated CD33+ cells. Data are presented as the mean ± SEM of 3 separate donors. (D) Fold change in expression of ARG1, NOS2, and IL10 (determined by RT-qPCR analysis) in cultured human BM cells. Expression was normalized to PPIA and is depicted for each donor (n = 5 separate donors, including the 3 donors from A–C). The absence of a bar indicates no detectable signal for the expression of either ARG1, NOS2, or IL10. Donor 1: female, age 29 years; donor 2: female, age 48 years; donor 3: female, age 13 years; donor 4: male, age 7 years; donor 5: male, age 12 years. *P < 0.05, by paired t test (B and C).