Unraveling the Immune Microenvironment in Classic Hodgkin Lymphoma: Prognostic and Therapeutic Implications

SIMPLE SUMMARY: Hodgkin lymphoma accounts for 10% of new lymphoma diagnoses and has generally high cure rates, although there is a need for new treatments in the relapsed setting. On the microscopic scale, neoplastic cells are believed to be in a constant cross-talk with their surrounding immune cells and shape a microenvironment that suppresses host’s anti-tumor immunity. In this review, we summarize findings regarding the role of each cell in the tumor microenvironment of classic Hodgkin lymphoma, with a focus on macrophages, and we describe ways in which the tumor cells manage to escape from the patient’s immune surveillance. Within this microenvironment, novel therapeutic targets have emerged, allowing for a personalized approach for patients with Hodgkin lymphoma. ABSTRACT: Classic Hodgkin lymphoma (cHL) is a lymphoid neoplasm composed of rare neoplastic Hodgkin and Reed–Sternberg (HRS) cells surrounded by a reactive tumor microenvironment (TME) with suppressive properties against anti-tumor immunity. TME is mainly composed of T cells (CD4 helper, CD8 cytotoxic and regulatory) and tumor-associated macrophages (TAMs), but the impact of these cells on the natural course of the disease is not absolutely understood. TME contributes to the immune evasion of neoplastic HRS cells through the production of various cytokines and/or the aberrant expression of immune checkpoint molecules in ways that have not been fully understood yet. Herein, we present a comprehensive review of findings regarding the cellular components and the molecular features of the immune TME in cHL, its correlation with treatment response and prognosis, as well as the potential targeting of the TME with novel therapies. Among all cells, macrophages appear to be a most appealing target for immunomodulatory therapies, based on their functional plasticity and antitumor potency.