Previously Funded Research

Nelson LaMarche, PhD

Yale University

Research Project:

Defining clinically targetable drivers of pathogenic myeloid cell development for NSCLC immunotherapy

Summary:

Lung cancer is the leading cause of cancer death worldwide. While immune checkpoint blockade immunotherapy has revolutionized treatment for lung cancer, only a small percentage of patients respond to this treatment. This is because the tumor microenvironment is filled with many immunosuppressive cell types called myeloid cells which prevent immune activation and tumor cell killing. Therefore, identifying ways to deplete myeloid cells from lung tumors or prevent their accumulation would be an important combination immunotherapy for lung cancer.

One important characteristic of myeloid cells is that they develop in the bone marrow and travel to tumors through the blood after being activated. Therefore, targeting myeloid cell development in the bone marrow is an unappreciated strategy for blocking myeloid cell immunosuppression in lung cancer.

We recently made the surprising discovery that a protein called interleukin-4 (IL-4) is produced in the bone marrow during lung cancer and promotes immunosuppressive myeloid cell development. Interestingly, IL-4 is a protein commonly associated with allergies, not cancer. We blocked this protein with a commonly used allergy medication in lung cancer patients and showed that this prevented myeloid cell development, activated the immune system, and reduced tumor size.

This was the first study to show that targeting myeloid cell activation in the bone marrow is a viable immunotherapy for lung cancer. It also indicated that targeting proteins typically associated with allergy could be a broad strategy for blocking myeloid cell development in lung cancer. This could open opportunities to repurpose many allergy medications for the treatment of lung cancer. This proposal will determine if other allergy-related proteins are produced in bone marrow during cancer that can be clinically targeted and explore additional signaling pathways in bone marrow that can be targeted to prevent myeloid cell development and immunosuppression during lung cancer.