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.
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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

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Figure 1

BRQ reverses the suppressive activity of MDSCs.

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BRQ reverses the suppressive activity of MDSCs. Female BALB/c mouse BM c...
Female BALB/c mouse BM cells were cultured with 40 ng/mL recombinant mouse (rm) G-CSF plus rmGM-CSF for 96 hours with or without 1 μM BRQ (Tocris). (A) Flow cytometric analysis of CD11b and Gr-1 expression in cultures treated with vehicle (Veh) or BRQ. (B) Percentage of CD11b+Gr-1+ cells. (C) Percentage of viable cells as determined by trypan blue staining and live cell quantification. (D) Percentage of apoptotic cells, as determined by annexin V and DAPI staining of vehicle- or BRQ-treated MDSCs. (E) CD4+ and CD8+ T cell proliferation following coculture with MDSCs generated with or without 1 μM BRQ (from Clear Creek) or 25 μM Lef. Splenocytes from naive syngeneic mice were used as a source of T cells and were stimulated with 1 μg/mL anti-CD3 (αCD3) mAb for 72 hours. Cell proliferation was measured using CellTrace Violet. (F) CD4+ and CD8+ T cell proliferation following coculture with MDSCs with or without BRQ in the absence or presence of 200 �M uridine. Data are presented as the mean ± SEM of 5 separate experiments (B and C), 6 separate mice (D), or triplicate determination (E and F). **P < 0.01 and ****P < 0.0001, by unpaired t test (B–D).