Expression of the Immunosuppressive Molecules PD-L1 and Galectin-1 by EBV+ Lymphoproliferative Disorders: Novel Candidates for Targeted Immunotherapy
Benjamin J Chen, Jing Ouyang, Mina L Xu, Hongbo Yu, Christopher DM Fletcher, Heather Sun, Margaret A Shipp, Scott J Rodig. Brigham and Women's Hospital, Harvard Medical School, Boston, MA; DFCI, Boston, MA; Yale School of Medicine, New Haven, CT; UMass Memorial Hospital, Worcester, MA
Background: Programmed cell death ligand 1 (PD-L1) and Galectin-1 (Gal1) are expressed by antigen-presenting cells and by select tumors that engage receptors on T cells to inhibit T-cell immunity. Upregulation of PD-L1 and Gal1 on cells is due, in part, to viral activation of AP-1 signaling molecules JunB and c-Jun. Targeted immunotherapy using humanized anti-PD-L1 and anti-PD-1 antibodies have yielded durable clinical responses in patients with solid tumors. Similarly, a Gal1 neutralizing antibody prevents Gal1-mediated apoptosis of EBV-specific CD8+ T cells that target EBV-infected B cells. We previously have shown that PD-L1 and Gal1 are upregulated in EBV+ PTLDs. In this study, we sought to expand the categories of lesions that may benefit from such targeted immunotherapy by examining additional EBV, HHV8, and immunodeficiency-related tumors for the expression of PD-L1 and Gal1 and their association with AP-1 activation.
Design: Whole tissue sections from EBV+ DLBCL of the elderly/immunodeficiency-related, plasmablastic lymphomas (PBL), primary effusion lymphomas (PEL), extranodal NK/T-cell lymphomas (ENKTCL), EBV+ Burkitt lymphomas (BL), nasopharyngeal carcinomas (NPC), HHV8+ Kaposi sarcomas (KS), and EBV-negative PTLDs were evaluated. Immunohistochemistry was performed using anti-PD-L1, anti-Gal1, anti-JunB, and anti-phospho-c-Jun (p-c-Jun) antibodies. Staining for each marker was scored positive if there was 2-3+/3+ staining intensity in greater than 20% of tumor cells.
Results: Robust staining for PD-L1 and Gal1 was observed in the majority of EBV+ DLBCL (100%, 69%, respectively), ENKTCL (100%, 80%), PBL (29%, 73%), and PEL (33%, 100%) along with concurrent expression of JunB and p-c-Jun. Most cases of EBV-negative PTLD and NPC strongly expressed PD-L1 (86% and 100%, respectively) but were negative for Gal1. Most cases of KS (78%) expressed Gal1 but only 1 case (7%) expressed PD-L1. In contrast, all EBV+ BL lacked both PD-L1 and Gal1 expression.
Conclusions: A broad group of EBV+ and HHV8+ tumors express levels of PD-L1 and Gal1 comparable to that observed for EBV+ PTLD with concomitant expression of AP-1 signaling markers JunB and p-c-Jun. These results suggest that PD-L1 and Gal1 expression is a general mechanism of immune evasion among viral-associated malignancies and expands the spectrum of tumors that are candidates for PD-L1 and Gal1-directed therapies.
Monday, March 4, 2013 2:15 PM
Proffered Papers: Section C, Monday Afternoon