Unraveling the Pro-Tumorigenic Myelopoiesis Driven by an IL-4 Signaling Axis in Bone Marrow

CRI is delighted to share the latest milestone achievement from CRI-supported investigators at Icahn School of Medicine at Mount Sinai: CRI-Bristol Myers Squibb Postdoctoral Fellow Nelson M. LaMarche, PhD, CRI Clinical Innovator Thomas Urban Marron, MD, PhD, and CRI SAC member Miriam Merad, MD, PhD. They have recently published their groundbreaking discovery in the prestigious science journal Nature. The research highlights the role of IL-4 signaling in bone marrow in production of pro-tumor myeloid cells. Based on these findings, the team has successfully initiated a clinical trial to treat non-small cell lung cancer patients with a combination of PD-1/PDL1 blocking antibodies and IL-4Rα blocker, Dupilumab.

What does the paper say?

In their recent findings, Dr LaMarche and colleagues revealed that immune cells in the bone marrow, specifically basophils and eosinophils, produce an immune cytokine called interleukin-4 (IL-4). This cytokine, IL-4, was found to play a crucial role in promoting the generation of immunosuppressive myeloid cells that support tumor growth. These macrophages, acting as pro-tumor cells, suppress the body’s natural anti-tumor immune responses. In experiments involving genetically engineered mice lacking basophils, the researchers observed significantly smaller tumors and a reduced number of macrophages in the lungs.

Applying this discovery to patients, Dr. Marron, initiated a clinical trial using Dupilumab—a drug that blocks the protein receptor for IL-4 in combination with a PD1 /PD-L1 checkpoint blockade to treat patients with relapsed or refractory non-small cell lung cancer (NSCLC). The trial showed promising results, with one of the six patients treated with the drug combination showing near complete response.

This study highlights the role of IL-4 in controlling the development of immune cells that suppress the immune system in cancer. The study also discovered a new way to combine treatments to block immune checkpoints in patients.

Read more about this fascinating discovery here.

Why is this important?

Myeloid cells play a crucial role in shaping tumor progression, at times by suppressing the body’s anti-tumor immune response. In the case of NSCLC, the tumor is infiltrated by macrophages that actively contribute to tumor development through various means. Unfortunately, these macrophages create a resistant environment, making current immunotherapies less effective in treating the tumor. The introduction of any therapy or drug capable of safely managing these tumor-associated macrophages could revolutionize the field, especially when combined with existing immunotherapies.

CRI Scientists:

CRI-Bristol Myers Squibb Postdoctoral Fellow Nelson M. LaMarche, PhD, Icahn School of Medicine at Mount Sinai is supported by the CRI Irvington Postdoctoral Fellowship to Promote Racial Diversity. He is working in the lab of Miriam Merad, MD, PhD, where he has identified two major populations of macrophages in NSCLC and is now working to define how these two populations respond to PD-1 immunotherapy, with the goal of identifying targetable pathways through which these cells could be manipulated to enhance the effectiveness of immunotherapy.

Thomas Urban Marron, MD, PhD, is the Director of the Early Phase Trials Unit (EPTU) at The Tisch Cancer Institute and Associate Professor of Medicine at Icahn School of Medicine at Mount Sinai, New York city. CRI recently awarded Dr. Marron a Clinical Innovator Award to support a clinical trial investigating the effect of IL-4 blockage in combination with PD-1 inhibition in the neoadjuvant setting for patients with non-small cell lung cancer.

CRI SAC member Miriam Merad, MD, PhD, is the Mount Sinai Endowed Chair in Cancer Immunology and the director of the Precision Immunology Institute at Icahn School of Medicine (PrIISM) at Mount Sinai in New York and the director of the Mount Sinai Human Immune Monitoring Center.  She is the corresponding author of the research article.

Oakley C. Olson, PhD, Columbia University, is supported by a CRI Irvington Margaret Dammann Eisner Postdoctoral Fellowship.