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.

Bring on the brequinar: an approach to enforce the differentiation of myeloid-derived suppressor cells

“…In this study, BRQ-treated MDSCs showed a decrease in the unfolded protein response pathway and downregulation of inducible NOS (iNOS) enzymes, both of which are mechanisms known to increase ROS. These observations provide evidence that reducing oxidative species may also facilitate myeloid differentiation ( 4 ). In another recent report, other mechanisms of BRQ have emerged that elicit direct action on malignant cells, including its ability to increase lipid peroxidation in the inner mitochondrial membrane ( 10 ).…”

“…In this issue of the JCI , Colligan et al addressed the concept of targeting MDSCs at the bone marrow progenitor phase in a series of preclinical studies ( 4 ). The authors focused on immunotherapy-resistant breast cancer, since MDSCs play a prominent role in this tumor type, lending future translational importance to the study ( 5 ).…”

“…Importantly, the data on BRQ showed pyrimidine synthesis in MDSCs as an important mechanism that suppressed T cell function, since T cell proliferation was restored when MDSCs were treated with BRQ ( 6 – 8 ). This mechanism was then validated using leflunomide, another DHODH inhibitor, and the effects of BRQ were reversible by the addition of uridine, which allowed cultured cells to bypass the endogenous pathway of pyrimidine synthesis that required DHODH ( 4 ).…”

“…Consequently, BRQ also reduced the ability of PMN-MDSCs to elicit a suppressive function on T cells and dampened the expression of multiple pathways and downstream functional mediators of MDSC biogenesis, including Arg1, iNOS, etc. ( 4 ). This feature is particularly attractive, as it suggests that BRQ targets both the differentiation and downstream functions of MDSCs in relevant models.…”

“…Finally, the authors showed that inhibition of MDSC biogenesis by BRQ was generalizable in both the murine 4T1 tumor model and in a human bone marrow culture system. This report represents an innovative application of DHODH inhibitors as a means to augment the efficacy of immune checkpoint blockade in resistant tumor models ( Figure 1 ) ( 4 ).…”