Follicular Lymphoma Microenvironment: An Intricate Network Ready for Therapeutic Intervention

SIMPLE SUMMARY: Follicular lymphoma is a paradigm of tumors that require the interaction between tumor and microenvironment cells to foster their development from initial steps to progression. Recent large-scale genome studies have uncovered multiple genetic alterations that cooperate with the lymphoma microenvironment to promote cell survival, proliferation and to facilitate tumor evasion from host immune system. Understanding the crosstalk between tumor B-cells and the microenvironment is fundamental to identify vulnerabilities that may offer novel therapeutic targets. This review highlights recent findings showing the effect of common genetic mutations modulating the cell composition and phenotype of the tumor microenvironment and the novel therapeutic perspectives to target these interactions. ABSTRACT: Follicular Lymphoma (FL), the most common indolent non-Hodgkin’s B cell lymphoma, is a paradigm of the immune microenvironment’s contribution to disease onset, progression, and heterogeneity. Over the last few years, state-of-the-art technologies, including whole-exome sequencing, single-cell RNA sequencing, and mass cytometry, have precisely dissected the specific cellular phenotypes present in the FL microenvironment network and their role in the disease. In this already complex picture, the presence of recurring mutations, including KMT2D, CREBBP, EZH2, and TNFRSF14, have a prominent contributory role, with some of them finely tuning this exquisite dependence of FL on its microenvironment. This precise characterization of the enemy (FL) and its allies (microenvironment) has paved the way for the development of novel therapies aimed at dismantling this contact network, weakening tumor cell support, and reactivating the host’s immune response against the tumor. In this review, we will describe the main microenvironment actors, together with the current and future therapeutic approaches targeting them.