PD-L1 and PD1 Expression in Lymphomas

Background

Binding of PD-1 with ligands (e.g. PD-L1) expressed on tumor cells or native antigen-presenting cells results in down-regulation of effector T cell function and represents a potent mechanism of immune evasion across a number of solid tumors and lymphomas especially classical Hodgkin lymphoma (CHL) and aggressive virus-associated B-cell lymphomas. Several biomarkers (different antibodies, gene amplifications and mutations) are being investigated for identifying patients who may benefit from PD-1 checkpoint blockade therapies. It is well known that tumors which strongly express PD-L1 have a high clinical response rate to PD1 blockade. We aimed at identifying the expression of PD-L1 and PD1 in a diverse group of lymphomas. There are several antibodies used to detect PD-L1 expression, however the concordance between these antibodies is not known. We have previously tested concordance of 2 anti-PD-L1 antibodies in histiocytoses [1], but data in lymphomas are lacking. In the current study, we measured PD-L1 expression in lymphoma biopsy samples using 3 antibodies to identify if there was concordance in expression patterns of PD-L1 in various subtypes of lymphomas.

Methods

Formalin fixed paraffin embedded tissues from 37 patients with lymphomas of B- and T-cell lineages (both EBV-positive and negative) were investigated for the expression of PD-1 (MRQ-22 antibody) and PD-L1 (MAB1561, SP142 and SP263) using automated immunohistochemical methods. Expression of PD-L1 on 5% or more lymphoma cells was considered positive.

Results

Neoplastic cells expression of PD-L1 was identified in 13/37 cases (35% of all cases). The strongest (3+/>50% cells) and consistent (4/4 cases) expression was observed in Hodgkin RS cells of CHL (2/2 nodular sclerosis and 2/2 lymphocyte depleted). Other B-cell lineage lymphomas positive for expression of PD-L1 included diffuse large B-cell lymphomas (5/9 DLBCL) and lymphomatoid granulomatosis (1/1 LYG). Small lymphocytic lymphoma (n=3), splenic marginal zone lymphoma (n=2) and follicular lymphomas (n=8) were all negative. One of four mantle cell lymphomas (MCL) was borderline (5% of cells) positive. One NK/T-cell lymphoma was strongly (>50% cells) positive; four peripheral T-cell lymphomas (PTCL) and one T cell lymphoblastic lymphoma were negative. PD-L1 expression was observed in both EBV- positive (2/4) and negative (2/3) malignancies. Concordance between any 2 anti-PD-L1 antibodies varied between 86 and 97% (Table 1) with all 3 Abs agreeing in 82%. PD-1 was expressed on malignant cells in 3 cases (2 PTCL and 1 DLBCL); reactive PD-1+ T-lymphocytes were absent in LD CHL and variably present in all other lymphomas.

Conclusions

Over-expression of PD-L1was detected in classic HD, diffuse large B cell lymphoma, NK/T cell lymphoma and lymphomatoid granulomatosis. A high concordance in detection of PD-L1 between three antibodies indicates little need for companion diagnostic kits, but correlation between clinical responses and level of PDL1 and PD1 expression in lymphoma should be established in future clinical trials.

References:

1. Gatalica, Z., et al., Disseminated histiocytoses biomarkers beyond BRAFV600E: frequent expression of PD-L1. Oncotarget, 2015.