Metabolic Reprogramming of Myeloid Cells to Enhance Cancer Immunotherapy - PROJECT ABSTRACT/SUMMARY Immunotherapy has revolutionized how oncologists treat cancer patients. One type of immunotherapy includes immune checkpoint inhibitors (ICIs), such as those that engage PD-1 on cytotoxic CD8+ T cells to bolster their effector functions. However, in several cancer types, single-agent therapy is moderately effective, but when combined with standard-of-care (SOC) chemotherapy, the combination regimen improves overall response rates. Therapeutic efficacy may be hampered by numerous barriers, including the immune suppressive tumor microenvironment (TME). One major cellular component of the TME includes myeloid-derived suppressor cells (MDSCs), which correlate with poorer survival outcomes and suppress antitumor activity of CD8+ T cells in response to these ICIs. To overcome these obstacles of immune suppression, we developed a novel approach to target MDSC ‘biogenesis’ in the bone marrow to mitigate their production and function, and boost ICI activity in mouse models of triple-negative breast cancer (TNBC), a cancer type that elicits a robust MDSC response. We identified a metabolic vulnerability in MDSCs and targeted that dependency using agents known as dihydroorotate dehydrogenase (DHODH) inhibitors. DHODH inhibitors block de novo pyrimidine metabolism and are being clinically tested as a therapy in acute myeloid leukemia. We found that combining the DHODH inhibitor, brequinar (BRQ), with PD-1 blockade significantly reduced tumor growth, and that therapeutic efficacy depended upon a reduction in MDSC suppressive activity. However, tumors still grew introducing two important gaps. First, it remains unclear how DHODH blockade ‘reprograms’ MDSC function and, secondly, it remains unclear how therapeutic efficacy can be further augmented. Regarding the first gap, in Aim 1 of the F99 phase, we will focus on the unfolded protein response (UPR) based on the rationale that we found that the UPR pathway is one of the top downregulated pathways in myeloid progenitors that give rise to MDSCs and that prior work in the field showed that the UPR is a key pathway by which MDSCs mediate their activities, particularly, via the transcription factor XBP1. Regarding the second gap, we propose to build on a SOC chemo-immunotherapy platform to augment antitumor responses. Therefore, in Aim 2 of the K00 phase, we will determine whether incorporating BRQ to a paclitaxel/anti-PD-1 monoclonal Ab regimen, which is clinically used in TNBC, bolsters CD8+ T cell responses and achieves durable antitumor immunity. Our central hypothesis is that DHODH blockade reprograms MDSCs toward less immune suppressive states through an XBP1-dependent mechanism in the UPR pathway. We further hypothesize that MDSC mitigation through this pathway will further sensitize TNBC to a SOC chemo-immunotherapy regimen. New advances gained from this research have the potential to inform the clinical design of novel, more effective combination immunotherapies.
