Cytokine-linked remodeling of the immune microenvironment is a hallmark of transformation in follicular lymphoma [bulkRNA-seq]

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 85 FL and transformed FL samples, including single-cell and bulk RNA-sequencing alongside spatial transcriptomics and proteomics. Upon transformation, GPNMB+ macrophages and fibroblasts with matrix-remodeling phenotypes increased while lymph-node organizing populations (e.g. follicular dendritic cells, CCL21-expressing fibroblastic reticular cells) were lost. Transformation was marked by altered spatial distribution of cytokines, impacting macrophage differentiation and T cell infiltration. This detection of secreted stromal and macrophage signals was 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.