Programmed death-1 ligands PD-L1 and PD-L2 show distinctive and restricted patterns of expression in lymphoma subtypes.

The success of immunotherapy using immune checkpoint blockade in solid tumors and in relapsed/refractory classical Hodgkin lymphoma and chronic lymphocytic leukemia holds promise for targeted therapy in hematologic malignancies. Because efficacy of immunomodulatory therapy is correlated with numbers of cells that express programmed death (PD-1) ligands, we evaluated the expression of PD-L1 and PD-L2 proteins using immunohistochemistry in more than 702 diagnostic lymphoma biopsies. In classical Hodgkin lymphoma, PD-L1 and PD-L2 were expressed in 82% and 41% of cases, respectively, and PD-L1 but not PD-L2 expression correlated with Epstein-Barr virus in tumor cells. PD-L1 staining was detected in 80% of anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma, and follicular dendritic cell sarcoma; 75% of nodular lymphocyte-predominant Hodgkin lymphoma; 53% of primary mediastinal large B-cell lymphoma; 39% of extranodal NK/T cell lymphoma; 26% of peripheral T-cell lymphoma; 10% of diffuse large B-cell lymphoma; and very rare examples of mantle, marginal zone, and small lymphocytic lymphomas. PD-L2 staining was present in 78% of primary mediastinal large B-cell lymphoma but in fewer cases in all other categories including 40% of follicular dendritic cell sarcoma and 7% of anaplastic large cell lymphoma. Our results confirm and extend prior studies of PD-L1 and provide new data of PD-L2 expression in lymphomas. The differential expression patterns in some tumor types and the expression of PD-L2 in the absence of PD-L1 raise the possibility of targeted therapy for additional subsets of patients with lymphoma.