Project Term
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Project Summary
EZB lymphomas, driven by BCL2 translocations and EZH2 mutations, induce macrophages to adopt a supportive role, essential for maintaining the malignant phenotype. This reprogramming suppresses phagocytosis and promotes pro-tumor activation, mediated by immune synapse signaling and cytokine release. Our study aims to identify molecular pathways involved in this macrophage reprogramming and explore restoring anti-tumor functions as a therapeutic approach.
Lay Abstract
Blood cancers, such as diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL), often relapse after initial treatments, making them difficult to treat long-term. Among these, EZB lymphoma, driven by specific genetic mutations (such as in the EZH2 gene), is especially challenging. These mutations not only fuel the growth of lymphoma B cells but also reprogram nearby immune cells, converting the whole lymphoma microenvironment to support Lymphomagenesis. A significant challenge in treating EZB lymphoma is our limited understanding of how these reprogrammed immune cells contribute to cancer growth, preventing us from effectively reversing this process.
Our immune system relies on specialized cells to fight disease, including macrophages. Often called “cellular cleaners,” macrophages detect, engulf, and destroy harmful or dying cells. However, EZB lymphoma cells manipulate macrophages, reprogramming them to support tumor growth rather than attack it. This transformation alters the shape and behavior of macrophages, converting them into tumor allies. Additionally, these modified macrophages disrupt other immune responses, especially those of T cells, which are essential for a strong immune defense. Specifically, they interfere with the interaction between T cells and B cells, weakening the body’s overall response to the lymphoma.
Our research seeks to understand how EZB lymphoma cells reprogram macrophages and whether this process can be reversed. To achieve this, we are using EZH2 inhibitors to inhibit EZH2 activity, we hope to restore macrophages to their original, cancer-fighting state. We are also exploring whether reactivating macrophages makes other treatments, like CD47-targeted therapies, more effective. CD47 is a protein that helps cancer cells evade detection by macrophages, so restoring macrophage function may improve the effectiveness of CD47-based therapies.
We are using patient-derived samples and advanced imaging techniques to observe how Taz affects macrophage behavior in real-time. Success in this project could lead to new combination therapies that engage the immune system to combat EZB lymphoma more effectively. This research aims to create better, long-lasting responses for patients and may also provide insights for treating other blood cancers, ultimately improving survival and quality of life for patients.
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