Follicular Lymphoma Transformation Is Characterized by Cytokine-Associated Remodeling of Stromal and Macrophage Compartments

Abstract Across cancer, one of the most frequent examples of histologic transformation is the evolution of follicular lymphoma to an aggressive large cell lymphoma. Despite recent progress, the understanding of the molecular and cellular underpinnings of transformation remains incomplete. In this study, we dissect the interplay of tumor and microenvironment cell populations across transformation through a multimodal investigation of 95 follicular lymphoma and transformed follicular lymphoma (tFL) samples, including single-cell and bulk RNA sequencing alongside spatial transcriptomics and proteomics, and validate findings across independent follicular lymphoma–tFL pairs. Upon transformation, fibroblasts and GPNMB+ macrophages increase, whereas lymph node–organizing follicular dendritic and CCL21+ fibroblastic reticular cells (FRC) are lost, resulting in an altered spatial distribution of cytokines that affects T-cell infiltration and macrophage differentiation and function. Secreted stromal and macrophage signals are further evident through noninvasive plasma proteomics. Taken together, our data reveal the expansion of macrophages and fibroblasts as key features of transformation with potential diagnostic and therapeutic implications. Significance: Single-cell and spatial profiling of indolent and tFL samples reveals transformation-associated microenvironment alterations, including increased GPNMB+ macrophages and fibroblasts and decreased follicular dendritic and CCL21+ FRCs. The altered chemokine landscape of tFL is detectable through plasma proteomics, affording potential diagnostic and therapeutic opportunities.