Towards Targeting the Follicular Lymphoma Microenvironment Follicular lymphoma (FL) is the second most common and still incurable form of B cell lymphoma. FL is a slow growing cancer that shows a unique dependence on a supportive microenvironment. The supportive niche also affects FL therapies. For example, inhibitors of BTK, PI3K, or BCL2 show exciting activity against aggressive lymphomas and chronic leukemia, but they have little activity against indolent FLs. We speculate that the FL microenvironment protects and sustains the malignant B cells and contributes to FL development, progression, and resistance to therapy. Conversely, we propose that disrupting interactions in the FL niche will be especially effective against FL. Our hypothesis is based on prior work by others and our own work on immune receptor mutations in FL (e.g. TNFSRF14 and EphA7) have revealed cell-cell interactions as key drivers and sustainers of FL biology. My lab has made major contributions to our understanding of the biology and genetics of FL. We built an accurate mouse model of FL and we and others have used this model to interpret the biological function of the most common FL drivers. For example, we reported on the role of epigenetic driver mutations in KMT2D, CREBBP, EZH2, we investigated FL cell metabolism, cell cycle control, aberrant mRNA translation, and the outstanding importance of immune receptors (e.g. TNFSRF14, b2M, EphA7) in FL biology. This work has been reported in an extensive series of high-impact publications. It has also led to several patent filings that protect experimental lymphoma therapies. We now propose a systematic assessment of the cellular composition of the FL microenvironment using cutting edge single-cell RNA sequencing on murine and human FLs. We want to understand how tumor genotype, indolent versus transformed disease stage, and therapy (esp. checkpoint inhibition) shapes the FL niche. We use single cell data to formulate specific hypotheses concerning cell-cell interactions and we use genetic and molecular biology tools to explore underlying mechanisms. Our goal is to identify opportunities to disrupt the supportive niche and to exploit this for new therapies. We have already had some success in this regard, and we engineered bi-functional antibodies and modified CAR-T cells that target interactions between malignant B cells and supportive niche elements. !
/ Public health relevance statement: We have made major contributions to understanding the molecular pathogenesis of follicular lymphoma (FL). We will now examine the unique dependence of FL cells on their supportive niche. We think this will reveal opportunities for intervention in this incurable cancer. !