A groundbreaking study published in Nature Cancer reveals why some patients with advanced HR+/HER2- breast cancer eventually develop resistance to CDK4/6 inhibitors, offering new strategies to enhance treatment effectiveness. The research, co-led by Lorenzo Galluzzi, PhD, Associate Professor in the Cancer Signaling and Microenvironment Research Program at Fox Chase Cancer Center, demonstrates for the first time how these targeted therapies can paradoxically create an immunosuppressive tumor microenvironment that promotes treatment resistance.
Novel Resistance Mechanism Uncovered
The multi-center study involving researchers from Fox Chase Cancer Center, Weill Cornell Medicine, and Cedars-Sinai Medical Center used mouse models to investigate the cellular mechanisms underlying CDK4/6 inhibitor resistance. The researchers discovered that some tumors respond to CDK4/6 inhibitors by releasing CCL2, a chemical that attracts gamma delta T-cells, which subsequently produce IL-17A.
"The tumor reacts to CDK4/6 by generating this immunosuppressive microenvironment," Galluzzi explained. "Radiation therapy prevents that from happening."
The study found that these immune chemicals alter the behavior of nearby macrophages, causing them to shift from tumor-fighting cells into a state that promotes tumor growth and treatment resistance, marked by the surface protein CX3CR1.
Clinical Validation in Human Patients
To validate their findings, researchers analyzed blood and tissue samples from human patients with HR+/HER2- breast cancer receiving CDK4/6 inhibitor treatment. The clinical data confirmed that patients with elevated levels of gamma delta T-cells experienced faster cancer relapse compared to those with normal levels.
Additionally, patients with higher concentrations of gamma delta T-cells in their blood and increased CCL2 levels in their plasma were more likely to experience cancer progression during CDK4/6 inhibitor therapy. High levels of IL-17A and gamma delta T-cells were also associated with more aggressive tumors and shorter survival rates.
Therapeutic Strategies to Overcome Resistance
The research identified three potential approaches to mitigate the immunosuppressive microenvironment and improve treatment outcomes:
Radiation Therapy
Mouse model studies demonstrated that adding radiation therapy to the standard combination of CDK4/6 inhibitors and hormonal therapy was more effective than standard care alone. The radiation therapy blocked signaling pathways responsible for increasing immunosuppressive cell populations.
Immune-Modulating Drugs
For patients unable to receive radiation therapy due to multiple tumors or proximity to sensitive organs, the study suggests targeting gamma delta T-cells and immunosuppressive macrophages with existing drugs that modulate the immune system.
Combination Approaches
"The takeaway is, let's give radiotherapy when we can," Galluzzi said. "But when we cannot, now we may have two different alternatives that we can use instead to make these inhibitors better."
Future Research Directions
Building on these findings, researchers at Fox Chase Cancer Center plan to conduct a follow-up study treating HR+/HER2- breast cancer patients scheduled for surgery with CDK4/6 inhibitors combined with drugs targeting gamma delta T-cells or immunosuppressive macrophages. They will examine post-surgical tumor samples to assess beneficial changes in the tumor microenvironment.
The research team ultimately aims to conduct clinical trials investigating whether these combination therapies prove more effective than current standard care. The gamma delta T-cells may also serve as predictive biomarkers to identify patients most likely to benefit from enhanced treatment approaches.
This research addresses a critical clinical need, as CDK4/6 inhibitors combined with hormonal therapy represent standard care for patients with advanced or metastatic HR+/HER2- breast cancer, yet many patients still experience treatment resistance and disease relapse.
