The immune microenvironment in Hodgkin lymphoma: T cells, B cells, and immune checkpoints

Abstract

Classical Hodgkin lymphoma is curable in the majority of cases with chemotherapy and/or radiation. However, 15-20% of patients ultimately relapse and succumb to their disease. Pathologically, classical Hodgkin lymphoma is characterized by rare tumor-initiating Reed-Sternberg cells surrounded by a dense immune microenvironment. However, the role of the immune microenvironment, particularly T and B cells, in either promoting or restricting Classical Hodgkin lymphoma growth remains undefined. Recent dramatic clinical responses seen using monoclonal antibodies against PD-1, a cell surface receptor whose primary function is to restrict T cell activation, have reignited questions regarding the function of the adaptive immune system in classical Hodgkin lymphoma. This review summarizes what is known regarding T cells, B cells, and immune checkpoints in classical Hodgkin lymphoma.

Figure 1.

Suppression of anti-tumor T cell responses by the CHL microenvironment. (A) RS cells and stromal cells secrete cytokines, chemokines, and other soluble immunomodulatory factors, such as IL-10, CCL17/TARC, galectin-1, and indoleamine 2,3-dioxygenase (IDO) which both recruit Th2 and regulatory CD4+ T cells and favor the differentiation of tumor-infiltrating T cells into regulatory and Th2 cells via the induction of lineage specific transcription factors Gata3 (Th2) and FoxP3 (Treg). (B) RS cells evade recognition by CD8+ and CD4+ T cells by downregulating expression of MHC-I and MHC-II in the majority of cases. They also express ligands that activate negative regulatory receptors present on T cells, such as PD-1. Conversely, RS cells are able to derive growth signals from CD40L, which is present on the majority of T cells within the microenvironment and activates CD40 on RS cells, driving NF-κB signaling and RS cell proliferation.

Figure 2.

A model for anti-tumor immunity in the setting of checkpoint blockade. (A) In solid tumors, anti-tumor immunity is mediated primarily by CD8+ T cell responses that are amplified in the setting of PD-1 blockade. However, in CHL this is mitigated by downregulation of MHC-I in the majority of cases. (B) This may predispose RS cells to killing by NK cells, which also express PD-1. Similarly, RS cell downregulation of MHC-II may limit CD4+ T cell responses following checkpoint blockade, but CD4+ T cells can also be primed by other APCs within the CHL microenvironment that do express MHC-II. Additionally, checkpoint blockade may impair the immunosuppressive function of infiltrating regulatory T cells, increasing productive T cell activation.