Preclinical study led by Roswell Park found a way to abate myeloid-derived suppressor cells (MDSCs) at their source
- Brequinar enhanced the antitumor activity of immune checkpoint inhibitors
- The approach inhibited both primary and metastatic disease
- The study appears in The Journal of Clinical Investigation
This work, published today in the The Journal of Clinical Investigation, opens the door for additional research and may have implications for cancer patients treated with immune checkpoint inhibitors or other immunotherapies in cases where MDSCs interfere with therapeutic efficacy.
Immune checkpoint inhibitors have improved survival outcomes for patients across cancer types; however, the effectiveness of these agents remain limited to certain patients. Multiple factors contribute to this, including the production of MDSCs. This population of blood cells are a mix of immature cells that form in the bone marrow in response to tumor growth.
“The infiltration of MDSCs at sites of tumor growth blocks the expansion and function of anti-cancer CD8+ T cells even in the face of immune checkpoint inhibitors. So strategies that interfere with MDSCs are likely to enhance immune checkpoint inhibitor outcomes,” says co-lead senior author Scott Abrams, PhD, Distinguished Member and Professor of Oncology in the Department of Immunology and Co-Leader of the Cancer Center Support Grant (CCSG) Tumor Immunology and Immunotherapy Program at Roswell Park.
Current strategies target MDSCs in the blood or tumor site, but do not adequately or effectively address their origin. As a result, these approaches are unlikely to offer long-lasting control of MDSC levels. To contend with this bottleneck in the field, Dr. Abrams and colleagues developed a different method that targets the MDSC formation at their point of origin — the bone marrow.
Known as differentiation therapy, this approach is typically used in acute myeloid leukemia (AML) to enforce maturation to normal cell populations. The study authors hypothesized that this concept could be similarly adapted to alter MDSC production by promoting their maturation. They repurposed brequinar, an oral dihydroorotate dehydrogenase (DHODH) inhibitor that has shown in vitro and in vivo anti-AML activity in preclinical models and is being tested in clinical trials of AML.
In the Roswell Park-led study, Sean Colligan, PhD, and Andrea Amitrano, PhD, co-first authors in the Abrams Lab, tested this agent alone and in combination with immune checkpoint inhibitors in preclinical models of triple-negative breast cancer (TNBC), which is characterized by high MDSC burden and immune checkpoint inhibitor resistance.
“Importantly, we found that brequinar treatment not only dampened the suppressive capacity of MDSCs by enhancing their maturation, but it also greatly boosted immune checkpoint inhibitor efficacy, inhibiting both primary and metastatic disease,” says co-lead senior author Michael Nemeth, PhD, Assistant Professor of Oncology in the Department of Immunology and Co-Chair of the Leukemia Translational Research Group at Roswell Park.
Given that MDSCs accumulate in many cancer types, this therapeutic concept uncovered by the Roswell Park-led team may prove valuable for the broader cancer community as well as immunotherapies beyond immune checkpoint inhibitors, such as cellular — or CAR T-cell — therapies.
“With FDA approval for the use of immune checkpoint inhibitors in a variety of cancer types, including TNBC, we believe our work is a significant advance in the field,” notes Dr. Abrams. “We have unveiled a novel and clinically feasible approach for potentially improving immune checkpoint inhibitor efficacy in patients with solid cancers where MDSCs play important roles in response to treatment.”
The study was funded by the Department of Defense, Breast Cancer Alliance, Roswell Park Alliance Foundation and Sklarow Memorial Trust.
Roswell Park Comprehensive Cancer Center is a community united by the drive to eliminate cancer’s grip on humanity by unlocking its secrets through personalized approaches and unleashing the healing power of hope. Founded by Dr. Roswell Park in 1898, it is the only National Cancer Institute-designated comprehensive cancer center in Upstate New York. Learn more at www.roswellpark.org, or contact us at 1-800-ROSWELL (1-800-767-9355) or ASKRoswell@RoswellPark.org.
Rebecca Vogt, Media Relations Specialist