Abstract IA6: Immune escape mechanisms in lymphoid malignancies.

Certain lymphoid malignancies utilize potent mechanisms to evade host anti-tumor immune responses including the AP-1-dependent overexpression of Galectin-1 (Gal1) and the genetic amplification and overexpression of the PD-1 ligands. Gal1 recognizes specific cell surface glycans (Gal1 β1 GlcNAc [N-acetyllactosamine] units on the branches of N- or O-linked glycans) on receptors such as CD45, CD43 and CD7 and induces the apoptosis of select T cell subsets – Th1, Th17 and cytotoxic T cells. Th2 cells and regulatory T (Treg) cells have different patterns of sialylation of cell surface glycoproteins, lack Gal1 ligands and resist Gal1-induced death. We recently found that malignant Reed-Sternberg (RS) cells in classical Hodgkin Lymphoma (cHL) and EBV-transformed malignant B cells in post-transplant lymphoproliferative disorders (PTLD) overexpress the secreted carbohydrate-binding lectin, Galectin-1 (Gal1). Gal1 overexpression by Hodgkin RS cells and EBV-transformed B cells promotes the immunosuppressive Th2/Treg-predominant, Th1/cytotoxic T cell-deficient micro-environment in cHL and PTLD. In both of these lymphomas with known constitutive activation of AP-1, Gal1 expression is driven, in large part, by an AP-1–dependent Gal1 enhancer. The AP-1-dependent expression of Gal1 is a useful diagnostic marker and circulating Gal1 levels have prognostic value. In addition, neutralizing Gal1 antibodies have promising immunomodulatory activity in in vitro assays and tumor models. Engagement of PD-1 receptors triggers T-cell “exhaustion” and the progressive loss of effector T-cell function and proliferative capacity. In certain cancers, the tumor cell expression of PD-1 ligands inhibits T-cell activation and promotes the apoptosis of tumor-specific T cells. We recently integrated high-resolution copy number data with transcriptional profiles and identified the PD-1 ligands, PD-L1 and PD-L2, as key targets of the 9p24.1 amplification in cHL and a related lymphoid malignancy, primary mediastinal large B-cell lymphoma (MLBCL). PD-1 ligand gene amplification was associated with increased protein expression in both lymphoid malignancies. In cHLs and MLBCLs, the extended 9p24.1 amplification region also included the JAK2 locus. JAK2 amplification increased JAK2 protein expression and activity and specifically induced PD-1 ligand transcription. Chemical inhibition of JAK2 decreased PD-1 ligand expression. These findings defined 9p24.1 amplification as a disease-specific structural alteration that increased both the gene dosage of PD-1 ligands and their induction via JAK2. Like Gal1, PD-L1 includes an AP-1-dependent enhancer which augments PD-L1 expression in lymphomas with constitutive activation of AP-1. In addition, Epstein-Barr virus (EBV) induces PD-L1 expression via AP-1 and EBV+ cHLs with diploid 9p24.1 and the majority of EBV+ PTLDs express detectable PD-L1. Therefore, AP-1- and EBV-driven malignancies with normal 9p24.1 copy numbers, including cHLs and most PTLDs, may also be amenable to PD-1 blockade. Taken together, these studies identify the PD-1 axis and Gal1 as promising therapeutic targets in certain lymphoid malignancies and define genetic bases for increased expression of these immunoregulatory molecules. For these reasons, clinical evaluation of PD-1 blockade alone and in association with JAK2 inhibition is planned and assessment of antibody-mediated Gal1 blockade is underway. Citation Format: Margaret A. Shipp. Immune escape mechanisms in lymphoid malignancies. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr IA6.