Extending the Survival of HR+ Breast Cancer Patients Receiving CDK4/6 Inhibitors by Targeting IL17-Producing Gamma Delta T Cells
Abstract
Overarching Challenges: Revolutionize treatment regimens by replacing them with ones that are more effective, less toxic, and impact survival; eliminate mortality associated with metastatic breast cancer. Background, Significance, and Innovation: Hormone receptor (HR)+ breast cancer (BC) is responsible for the majority of BCs (>80%) in the U.S. Standard treatment for early-stage, localized BC includes surgery, endocrine therapy +/- chemotherapy depending on risk assessment. Conversely, patients with advanced/metastatic HR+ BC currently receive cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) together with endocrine therapy as a first-line intervention, reflecting a recent change in clinical practice driven by the discovery that CDK4/6i mediate considerable anticancer activity in these patients. Unfortunately, tumors treated with CDK4/6i and endocrine therapy eventually come back in more than 45% of patients. When this happens, patients receive further lines of treatment, most often including chemotherapy which is highly toxic, and provide only marginal benefits on survival. Clearly, there is a large unmet need for therapeutic approaches that reduce the mortality of women with advanced/metastatic HR+ BC. Specifically, >30,000 women die of advanced/metastatic HR+ BC every year in the U.S. (>500,000 worldwide), and this proposal ultimately aims at reducing the mortality of this large patient population. While CDK4/6i have been developed as drugs that stop the replication of BC cells and hence delay tumor growth, accumulating preclinical evidence suggests that CDK4/6i can also activate the patient’s immune system to target the tumor. We hypothesize that that the clinical benefits of CDK4/6i in women with advanced/metastatic HR+ BC involve the initiation of a tumor-targeting immune response whereby the immune cells of the patient begin to kill BC cells. If this is true, then: (1) resistance to CDK4/6i may involve the inhibition of immune responses elicited by CDK4/6i against BC cells; and (2) the efficacy of CDK4/6i may be increased by combining these drugs with other agents that promote tumor-targeting immune responses. In strong support of this notion, we have already demonstrated that radiation therapy (RT), which is also capable of educating the patient’s immune system against cancer, can be efficiently combined with CDK4/6i, leading to an investigator-initiated clinical trial testing the same approach in patients with advanced/metastatic HR+ BC (CIMER, NCT04563507). Moreover, using an innovative mouse model of HR+ BC that recapitulates the main features of HR+ BC in women, we have identified a subpopulation of immune cells called gamma delta T cells that limits the efficacy of CDK4/6i. Objective: The objective of this project is to identify the mechanisms through which gamma delta T cells limit CDK4/6i efficacy in patients with advanced/metastatic HR+ BC. The Principal Investigators of this proposal are one translational scientist (Galluzzi) and one computational biologist/functional geneticist (Knott) who joined forces to dissect the impact of gamma delta T cells producing the immunosuppressive factor interleukin 17A (IL17A) on the response of HR+ BC to CDK4/6i. To this aim, they have assembled a multidisciplinary team of biologists, oncologists, bioanalysts, and patient advocates to rapidly translate the progress made in this project toward clinical applications. Specific Aims: (1) Determining the impact of gamma delta T cells on the mouse and human HR+ BC microenvironment. (2) Mechanistically dissecting the impact of gamma delta T cells on the response of mouse HR+ BCs to CDK4/6is. (3) Elucidating the impact of gamma delta T cells on the immune tumor microenvironment and disease outcome in HR+ BC patients receiving CDK4/6is. Impact: Taken together, the studies proposed herein will elucidate the impact of IL17A-producing gamma delta T cells on the immunological microenvironment of HR+ BC and clarify the p
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210506
Entities
People
- Lorenzo Galluzzi
Organizations
- United States Army
- Weill Cornell Medicine