Expression of the immune checkpoint receptor TIGIT in Hodgkin\u2019s lymphoma

Wenchao Li,Doris Höflmayer,Franziska Büscheck,Björn Wellge,Niclas C Blessin,Jakob R Izbicki,Tim Mandelkow,Ria Uhlig,Frank Jacobsen,Laura Pott,Ronald Simon,Claudia Hube‐Magg ,Eike Burandt,Till Krech,Guido Sauter,Martina Kluth,David Dum,Stefan Steurer,Sarah Minner,Waldemar Wilczak,Georgia Makrypidi‐Fraune ,Corinna Wittmer,Kristine Fischer,Nicolaus F Debatin,Maximilian Lennartz,Andreas M Luebke,Andrea Hinsch

doi:10.1186/s12885-018-5111-1

Abstract

Hodgkin’s lymphoma (HL) is characterized by a high background of inflammatory cells which play an important role for the pathogenesis of the disease. T cell immunoreceptor with Ig and ITIM domains (TIGIT) is an inhibitory immune checkpoint receptor and a putative target for novel immunotherapies. To study patterns of TIGIT expression in the T cell background surrounding malignant cells including Hodgkin cells, Reed-Sternberg cells and histiocytic cells, a microenvironment (ME) tissue microarray (TMA) was constructed from tissue punches measuring 2 mm in diameter obtained from formalin-fixed tissue samples of Hodgkin’s lymphoma lymph nodes (n = 40) and normal human tonsil (n = 2). The ME-TMA was stained by brightfield and fluorescence multiplex immunohistochemistry (IHC) to evaluate expression levels of TIGIT and PD-1 as well as standard lymphocyte markers (CD3, CD8, CD4, FOXP3) in the lymphocytic background. All analyzed cases of HL contained 9–99% (median: 86%) of TIGIT+ lymphoid cells. In general, TIGIT localized to the same cells as PD-1. Strikingly, expression levels of TIGIT and PD-1 were highly variable among the analyzed samples. Highest levels of TIGIT and PD-1 were found in one sample of nodular lymphocytic-predominant HL (NLPHL). In conclusion, TIGIT expression is highly variable between patients with Hodgkin’s lymphoma. Our results encourage further studies evaluating the role of TIGIT as a target for immunotherapies in Hodgkin’s lymphoma.

Highlights

Hodgkin’s lymphoma (HL) is a malignant transformation of B cell origin that accounts for about 20–30% of lymphomas in Western societies [1,2,3]
Additional experiments with serial dilutions of the TIGIT antibody confirmed the presence of T cells with extraordinary high levels of TIGIT expression in nodular lymphocytic-predominant HL (NLPHL) (Additional file 1: Fig. 1 Representative images of CD3, TIGIT and PD-1 staining in nodular lymphocyte predominance HL (NLPHL), nodular sclerosis classical HL (NSCHL), mixed cellularity classical HL (MCCHL) and lymphocyte rich classical HL (LRCHL)
All 40 HL analyzed in our study showed detectable TIGIT expression in all types of CD3 positive T cells including CD8 cytotoxic T cells, CD4 positive T helper cells, and FOXP3 positive regulatory T cells

Summary

Introduction

Hodgkin’s lymphoma (HL) is a malignant transformation of B cell origin that accounts for about 20–30% of lymphomas in Western societies [1,2,3]. The majority of Hodgkin’s lymphoma patients are curable with a multi-agent chemotherapy and/ or radiotherapy protocol, about 10–20% of patients develop therapy refractory disease [4]. Current clinical trials provide first evidence that immune checkpoint inhibitors targeting the PD-1/PD-L1 axis may hold promise in these refractory or relapsed Hodgkin’s lymphomas [5,6,7]. T cell immunoglobulin and ITIM domain (TIGIT), a co-inhibitory transmembrane glycoprotein of the poliovirus receptor (PVR)/−nectin superfamily, is another interesting candidate for novel checkpoint therapies [8, 9]. In mouse models and ongoing clinical studies, blockade or ablation of TIGIT, alone or in

Methods

Results

Conclusion