Heterogeneity Fair: Commentary to Menter and Tzankov “Lymphomas and Their Microenvironment: A Multifaceted Relationship”

Abstract

The relevance of the tumor microenvironment in lymphomas is elegantly depicted and discussed in the review article by Thomas Menter and Alexandar Tzankov, published in December 2019 [1]. Most of the influence cast on malignant clones by the tumor-associated microenvironment (TME) stems from the direct activity of immune cells, which are the primary components of the TME in most malignancies, and by the well-represented, yet poorly characterized constellation of mesenchymal elements. Immune cells of the TME are intimately involved in an "arm wrestling" between anti-tumor immune responses and orchestration of immune escape-promoting conditions. In their review, the authors decline the diversified nature of immune players populating the TME of classic Hodgkin lymphoma, non-Hodgkin low-and highgrade B-cell lymphomas, and peripheral T-cell lymphomas, focusing on the multifarious network of cytokines, chemokines, and growth factors that dynamically influence the malignant clone proliferative and survival dynamics and/or reshape the surrounding tissue microarchitecture in favor of a tumor-promoting cell niche.Although the cellular immune and mesenchymal players taking part to the instruction of a tumor-supportive microenvironment in lymphomas predominantly display the same phenotypes and functional activation states of those populating the TME of epithelial cancers (e.g., different subsets of effector and regulatory T cells; tumorassociated macrophages, cancer-associated fibroblasts), a further level of complexity has to be attributed to the lymphoma TME, which is intrinsic to the lymphoid nature of the malignant clones. Apart from the special position of classic Hodgkin lymphoma with very complex TME interactions and dependence as comprehensively summarized by Menter and Tzankov [1], lymphomatous clones show phenotypic and functional hallmarks of mature lymphocytes, which for most subtypes allow their characterization as malignant proliferations of elements normally populating specific immune contextures, such as the germinal center (GC), the mantle or marginal zones, or mucosal epithelial-immune interfaces [2]. This evidence implies that the TME associated with lymphomatous clones is subjected to functional polarization spurs