Classical Hodgkin lymphoma is curable in the majority of cases with chemotherapy and/or radiation. Thomas Hodgkin’s initial description of “morbid experiences of the absorbent glands and spleen” 1 the underlying pathophysiology of this eponymous disease remains highly enigmatic. While it has been established that this malignant Reed-Sternberg (RS) cells of classical Hodgkin lymphoma (CHL) are of B cell origin 2 3 these cells comprise only a small percentage of CHL tumor bulk while the remaining tumor microenvironment is usually rich in T cells non-malignant B cells granulocytes eosinophils and stromal cells. The contribution of the immune microenvironment to CHL pathogenesis remains incompletely defined; however the recent success of novel treatments aimed at amplifying anti-tumor T cell responses suggests a potential therapeutic role for the immune system in this disease.4 5 This review will highlight both the relative contribution of non-malignant T and B cells to the pathogenesis and prognosis of CHL as well as the role of negative regulatory immune checkpoints in CHL pathophysiology and therapeutic potential. T cells in CHL: friends or foes? The role of non-malignant T cells in CHL pathogenesis and treatment remains poorly comprehended. T cells are thought to suppress the development and growth of lymphomas; the increased NK314 incidence of lymphomas in patients receiving long-term immunosuppressants as well as immunodeficient mice supports this hypothesis.6-8 The presence of multiple tumor-infiltrating T cells “rosetting ” but failing to eliminate malignant RS cells has been well-described in CHL and is highly suggestive of an ineffectual T cell response in this disease.9 10 This has been complemented by the demonstration of impaired proliferative responses to mitogenic stimuli in peripheral blood lymphocytes isolated from CHL patients.11 What explains the impaired T cell responses seen in CHL? First the T cells that accumulate within the CHL microenvironment are largely skewed towards differentiation into either Th2 cells or regulatory T cells (Tregs).12-15 This accumulation is driven NK314 by a combination of selective recruitment as well as intratumoral functional reprogramming.16 RS cells produce a variety of Th2 and Treg-selective chemoattractants including CCL17/TARC 17 CCL22 18 NK314 CCL5 19 20 IL-4 IL-5 IL-10 and IL-13.15 21 22 Production of these chemoattractants is associated with inferior responses to therapy.23 24 Additionally RS cells secrete factors known to induce functional reprogramming of tumor-infiltrating T cells into Th2 cells and Tregs such as galectin-1 25 macrophage migration inhibitory factor29 and IL-7.30 Stromal cells within the CHL microenvironment also recruit immunosuppressive myeloid-derived suppressor cells and Tregs by secreting factors such as indoleamine 2 3 dioxygenase (IDO)31 (Determine 1 Determine 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 ( … Second effector T cells in CHL display features of chronic ineffectual antigen encounter a phenomenon known as T cell “exhaustion” characterized by the upregulation of unfavorable regulatory receptors such as the immunoglobulin superfamily member Programmed Death 1 (PD-1; CD279). PD-1 upregulation was initially characterized in models of chronic viral contamination32 33 but is also seen in multiple lymphomas including diffuse large B-cell lymphoma and follicular lymphoma.34 35 In CHL the expression of PD-1 on T cells Rabbit polyclonal to ALX3. is likely driven by constitutive upregulation of its ligands PD-L1 and PD-L2 on RS cells36 (Determine 1 Accordingly the NK314 presence of PD-1+ T cells both in the microenvironment and in the peripheral blood is a negative prognostic factor in CHL.37 38 Finally impaired anti-tumor immunity in CHL may be due to an inability of T cells to recognize RS cells. RS cells frequently lack expression of MHC-I and NK314 MHC-II which are required for antigen recognition by CD8+ and CD4+ T cells respectively. This can occur secondary to mutations such as in the epigenetic mechanisms at the CIITA promoter leading to decreased transcription.42 While T cells in CHL are rendered incapable of mediating anti-tumor responses there is some evidence to suggest that they may actually support RS cell growth and survival. CHL has been noted to develop during the immune response to active viral infections such as acute Epstein-Barr virus mediated mononucleosis.