Cell crosstalk within lymphoma tumor microenvironment: follicular lymphoma as a paradigm.

Follicular lymphoma (FL) is an indolent yet incurable germinal center B-cell lymphoma retaining a characteristic follicular architecture. FL tumor B cells are highly dependent on direct and indirect interactions with a specific and complex tumor microenvironment (TME). Great progress has been recently made in describing the heterogeneity and dynamics of FL-TME and in depicting how tumor clonal and functional heterogeneity rely on the integration of TME-related signals. Specifically, FL-TME is enriched for exhausted cytotoxic T cells, immunosuppressive regulatory T cells of various origins, and follicular helper T cells overexpressing B cell and TME reprogramming factors. FL stromal cells have also emerged as crucial determinants of tumor growth and remodeling, with a key role for deregulated chemokines and extracellular matrix composition. Finally, tumor associated macrophages play a dual function, contributing to FL cell phagocytosis and to FL cell survival through BCR long-lasting activation. The resulting tumor-permissive niches show additional layers of site-to-site and kinetic heterogeneity, which raise questions about the niche of FL-committed precursor cells supporting early lymphomagenesis, clonal evolution, relapse, and transformation. In turn, FL B cell genetic and non-genetic determinants drive the reprogramming of FL immune and stromal TME. Therefore, offering a functional picture of the dynamic crosstalk between FL cells and TME holds the promise of identifying the mechanisms of therapy resistance, stratifying patients, and developing new therapeutic approaches capable of eradicating FL disease in its different ecosystems.