Evaluation of the diagnostic and prognostic value of PDL1 expression in Hodgkin and B-cell lymphomas

Summary

Activation of the programmed death 1 (PD1)/PD1 ligand (PDL1) pathway is important for tumor cells to escape from immune control. The clinical efficacy of therapeutic modulation of the PD1-PDL1 pathway has been recently shown in classical Hodgkin lymphoma (cHL), but little is known about the frequency and diagnostic and prognostic importance of PDL1 expression in lymphomas. The available anti-PDL1 antibody clones E1L3N and SP142 were compared, and a large cohort of Hodgkin lymphomas (n = 280) and B-cell lymphomas (n = 619) was examined for PDL1 using E1L3N. The results were correlated with the expression of other phenotypic markers, interphase fluorescence in situ hybridization data of the 9p24.1 region (PDL1 locus), and the clinical outcome. PDL1 was expressed on more than 5% of tumor cells in 70% of cHL, 54% of nodular lymphocyte-predominant Hodgkin lymphoma, and 35% of primary mediastinal B-cell lymphomas; in the latter, PDL1 expression correlated with PDL1 gains (ρ = 0.573). PDL1 was expressed in 31% of primary diffuse large B-cell lymphomas (DLBCLs), whereas most other entities did not express PDL1. In cHL, expression of PDL1 correlated with increased numbers of granzyme + T cells (ρ = 0.251) and CD68 + macrophages (ρ = 0.221) but with decreased numbers of FoxP3 + T cells (ρ = 0.145). In activated B-cell–like DLBCL, PDL1 positively correlated with PD1 + T cells, whereas an inverse correlation with FoxP3 + T cells was seen in the germinal center B-cell–like DLBCL. PDL1 expression can be diagnostically valuable in some gray zones around DLBCL and cHL; it identifies an “immune escape” cluster of cHL and activated B-cell–like DLBCL with increased granzyme + and PD1 + T cells and macrophages and decreased regulatory T cells.

Introduction

The programmed death 1 (PD1)/PD ligand (PDL) pathway is an important checkpoint for the regulation of T-cell–mediated immune responses [1]. It consists of the transmembrane protein PD1/CD279 itself and its 2 ligands PDL1 (B7-H1, CD274) and PDL2 (B7-DC, CD273). These PDLs activate PD1, which results in a reversible inhibition of T-cell activity and proliferation also known as T-cell exhaustion or anergy. This mechanism plays an important physiological role in preventing placenta infiltration by T cells [2] and maintaining self-tolerance [3], which has been verified in animal studies of pd1 knock-out mice developing several autoimmune diseases [4].

Unfortunately, malignancies also make use of the immunosuppressive effects of the PD1-PDL pathway [5], which is to a part reflected by high levels of PD1-positive tumor infiltrating T-cells. Besides, several tumors are known to express PDL1, being one of the mechanisms of building up a defense line against tumor-infiltrating lymphocytes (TILs) [6]. This applies not only to solid tumors such as lung or breast cancer but also to hematolymphoid neoplasms such as angioimmunoblastic T-cell lymphoma, follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), and classical Hodgkin lymphoma (cHL), especially the nodular sclerosis subtype [7], [8]. Amplifications of the PDL1 gene locus on 9p24.1 are recurrent in the last 2 entities [9] further underscoring the importance of that pathway. PDL1 expression by immunohistochemistry has been demonstrated in some of the lymphomas listed above only in smaller cohorts or with antibodies shown to more poorly perform so far [10], [11]. Because of the fact that intrinsic cancer-specific T cells might be thwarted by PD1-PDL1 interactions [12], targeting PDL1 has become a new approach in tumor therapy [13]. Recently, first very promising results of PD1-PDL1 blockade have been reported in cHL, melanoma, and non–small cell lung cancer [14], [15], [16].

So far, the question whether expression of PD1 and PDL1 by immunohistochemistry might also be of diagnostic or prognostic importance in lymphomas has not been answered on larger collectives. It was our aim to investigate the expression of PDL1 at large scale in cHL and various B-cell lymphoma subtypes to draw conclusions both for diagnostic and potential clinicopathological applications.