Follicular Lymphoma Transformation is Characterized by Cytokine-associated Remodeling of Stromal and Macrophage Compartments
Nicholas J. Haradhvala, Stephanie Pei Tung Yiu, Laura Beckmann, Sam Sadigh, Zachary Leibowitz, Erik Landolsi, Santiago Rivero, Stephanie L. Deng, Sabrina Hu, Mingzeng Zhang, Daniel Filip, Amber Pospistle, Yao Yu Yeo, Katie Maurer, Johan Gustafsson, Kai Stewart, Vignesh Shanmugam, McKayla Van Orden, Wesley S. Lu, Shuqiang Li, Kenneth J. Livak, Huaying Qiu, Ankit Basak, Alex K. Shalek, Brian P. Danysh, Mikaela McDonough, Satyen H. Gohil, Yue Ren, Yinglu Zhou, Donna S. Neuberg, Svitlana Tyekucheva, Scott J. Rodig, Eric D. Jacobsen, Marek Mraz, Mark A. Murakami, Habibe Kurt, Catherine J. Wu, Gad Getz, Sizun Jiang, Erin M. ParryAbstract
Across cancer, one of the most frequent examples of histologic transformation is the evolution of follicular lymphoma (FL) to an aggressive large cell lymphoma. Despite recent progress, understanding of the molecular and cellular underpinnings of transformation remains incomplete. Here, we dissect the interplay of tumor and microenvironment cell populations across transformation through a multimodal investigation of 95 FL and transformed FL (tFL) samples, including single-cell and bulk RNA-sequencing alongside spatial transcriptomics and proteomics, and validate findings across independent FL-tFL pairs. Upon transformation, fibroblasts and GPNMB+ macrophages increase while lymph-node organizing follicular dendritic and CCL21+ fibroblastic reticular cells were lost, resulting in an altered spatial distribution of cytokines that impacts T cell infiltration and macrophage differentiation and function. Secreted stromal and macrophage signals were further evident by non-invasive plasma proteomics. Taken together, our data reveal expansion of macrophages and fibroblasts as key features of transformation with potential diagnostic and therapeutic implications.