Angioimmunoblastic T-cell lymphoma: Immune modulation as a therapeutic strategy

Angioimmunoblastic T-cell lymphoma (AILT) is a peripheral T-cell lymphoma with distinct clinical features and pathobiology [1]. It most commonly afflicts older patients and frequently presents with peripheral lymphadenopathy, hepatosplenomegaly, skin rash, and constitutional symptoms, thus distinguishing it from other peripheral T-cell lymphomas [2]. Patients often exhibit some degree of immunodeficiency, polyclonal hypergammaglobulinemia, and other hematological abnormalities which are likely related to abnormal immune regulation [3]. AILT usually responds to anthracycline-based chemotherapy, but has a low 5-year survival due to short-lived responses and a high incidence of infectious complications [2]. These poor outcomes have led to interest in novel approaches such as the addition of rituximab to anthracycline therapy, interferon, and more recently bevacizumab [4 – 6]. Unfortunately, while mechanistically interesting, these strategies have yet to significantly impact the disease. Considering the poor outcome of standard treatment in AILT, the results reported by Advani and colleagues in this journal are interesting and warrant further investigation [7]. In this retrospective analysis of 12 patients with AILT, 10 of whom received prior steroids and/or chemotherapy, the authors report 8 responders including 2 complete remissions with single agent cyclosporine. Although the patient numbers are small, the median (range) response duration of 13 (1–120þ) months is noteworthy and paves the way for further exploration of immunomodulatory therapy in this disease. These exciting albeit preliminary results with cyclosporine suggest a role for T-cell activation in the biology of AILT. Advani and colleagues provide a thoughtful model in which they propose that cyclosporine may act by inhibiting deregulated T-cell activation through the calcineurin-nuclear factor of activated T-cell (NF-AT) signaling pathway. This is an appealing hypothesis when considered within the context of the pathobiology of AILT. In this regard, the neoplastic T-cells in AILT are present in a marked inflammatory background with high endothelial venules (HEV) and expanded dendritic meshworks [1]. These cells have a T-helper cell phenotype expressing CD3 and CD4 and appear to be of germinal center origin (known as follicular B helper T (TFH) cells), a derivation supported by their coexpression of CD10 and BCL-6 [8,9]. It is notable that normal TFH cells produce high levels of the chemokine CXCL13 following costimulation through the CD28 and T-cell receptors (TCR), and that neoplastic T-cells in AILT have recently been shown to express CXCL13 [8,9]. Biologically, CXCL13 is important for the entry of B-cells into lymphoid follicles, stimulates expansion of follicular dendritic cells and participates in B-cell development and activation [10]. Thus, dysregulated CXCL13 production by the neoplastic T-cells likely accounts for key characteristics of AILT including expansion of dendritic meshworks and dysproteinemia. These pathobiological characteristics of AILT support the premise of abnormal immune regulation including B-cell and neoplastic T-cell activation. While deregulated T-cell activation could occur as the primary pathogenetic event, it is intriguing to hypothesize that the initiating event is antigen driven, as described in some marginal zone lymphomas of the stomach and spleen [11,12]. In considering this notion, a prominent histological feature of AILT is