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 7

BRQ inhibits the development of MDSCs from BM myeloid progenitors.

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BRQ inhibits the development of MDSCs from BM myeloid progenitors. (A) P...
(A) Proliferation of activated CD4+ or CD8+ T cells following coculturing with GMP-derived MDSCs. Unstim, unstimulated. (B) scRNA-Seq experiments were performed on c-Kit+ BM cells isolated from NTB mice or 4T1-bearing mice treated with vehicle or BRQ. For each experimental group, 3 biologic replicates were pooled. GSEA of the REACTOME UPR pathway comparing Veh-GMPs with NTB-GMPs (left) and BRQ-GMPs with Veh-GMPs (right). (C) Heatmap showing up- and downregulation of UPR pathways (P < 0.01, FDR < 0.25) in GMPs, based on the indicated comparisons. (D) GSEA of the Pathway Interaction Database (PID) Cdc42 signaling pathway comparing Veh-GMPs versus NTB-GMPs (left) and BRQ-GMPs versus Veh-GMPs (right). (E) Heatmap showing up- and downregulation of pathways related to RhoGTPase signaling (P < 0.01, FDR < 0.25) in GMPs, based on the indicated comparisons. (F) GSEA of the Kyoto Encyclopedia of Genes and Genomes (KEGG) leukocyte migration and the REACTOME neutrophil degranulation pathways comparing BRQ-GNs and Veh-GNs. Data in A are presented as the mean ± SEM of triplicate determinations from 2 separate mice. ***P < 0.001, by unpaired t test. In B, D, and F, the normalized enrichment score, FDR (q), and nominal P value are shown. NES, normalized enrichment score; Neg., negative; Pos., positive.