This observation suggests that the relative role of individual checkpoint molecules may considerably vary between different inflammatory diseases. 100%. The black bar shows the TIGIT?:?PD-1 expression ratio. Gc.: germinal centre; To: tonsil; P: patient. 5160565.f4.zip (241K) GUID:?DD80FCFC-A9F0-4001-AEDF-E422306BE698 Data Availability StatementThe data used to support the findings of this study are available from the corresponding author upon request. Abstract TIGIT is an inhibitory immune checkpoint receptor and a putative target for novel immune therapies. Here, we analysed two different types of tissue microarrays of healthy lymphatic and various inflamed tissues, colorectal and lung cancers, as well as 1700 tumour samples from 86 different tumour entities for TIGIT and/or PD-1 by bright field and/or multiplex fluorescence immunohistochemistry. TIGIT was detected in CD8+ cytotoxic T cells, CD4+ T helper cells, FOXP3+ regulatory T cells, and NK cells, but not in CD11c+ dendritic cells, CD68+ macrophages, and CD20+ B lymphocytes. TIGIT expression paralleled that of PD-1. More than 70% of TIGIT+ cells were PD-1+, and more than Haloperidol hydrochloride 90% of the PD-1+ cells were TIGIT+. Expression varied between different tissue compartments. TIGIT expression in tonsil gradually increased from the interfollicular area over the marginal/mantle zone to the germinal centre in all T cell subtypes. In inflammatory diseases, the strongest expression of TIGIT/PD-1 was found in Hashimoto thyroiditis. TIGIT+ lymphocytes were seen in all 86 BMP2 different tumour entities with considerable high variability Haloperidol hydrochloride of TIGIT positivity within and between different cancer entities. Particularly, high densities of TIGIT+ lymphocytes were, for example, seen in squamous cell cancers of various origins. In summary, the variable expression levels of TIGIT and PD-1 in cell types and tissue compartments illustrate the high complexity of immune microenvironments. The high frequency of TIGIT (and PD-1) expressing lymphocytes in cancers highlights considerable opportunities for cotargeting with checkpoint inhibitors. 1. Introduction Novel immune therapies using antibodies against immune checkpoint receptors, such as cytotoxic T lymphocyte antigen-4 (CTLA-4) and cell death protein-1 (PD-1), have demonstrated remarkable clinical efficiency in different tumour types, including metastatic melanoma, lung cancer, renal, and bladder carcinoma [1C3]. It is anticipated that blockade of other inhibitory immune checkpoint receptors will provide further therapeutic options. T cell immunoglobulin and ITIM domain (TIGIT), a coinhibitory transmembrane glycoprotein of the poliovirus receptor (PVR) family, is another interesting checkpoint receptor. Only recently, it was suggested that anti-TIGIT drugs might be associated with less autoimmune-like toxicity, making TIGIT an appealing target for new cancer immunotherapies [4, 5]. TIGIT was first described as a T cell and natural killer (NK) cell-specific surface protein in 2009 2009 [6C8]. TIGIT expression is restricted to T lymphocytes and highly expressed in effector and regulatory CD4+ T cells, follicular helper CD4+ T cells, effector CD8+ T cells, and NK cells [6, 7, 9C12]. Tumour infiltrating lymphocytes (TILs) expressing TIGIT have been demonstrated in several tumour types such as nonsmall cell lung cancer, colorectal carcinoma, melanoma, and acute myeloid leukaemia [9, 13, 14]. Although the downstream signalling cascade of TIGIT has not been clarified, there is evidence that TIGIT negatively regulates T cell activity through downregulation of T cell receptor expression [15C17]. In mouse models and on-going clinical studies, blockade or ablation of TIGIT, alone or in combination with blockade of PD-1, can restore tumour suppressive effects [4, 9, 13, 18, 19]. These findings indicate that TIGIT, similar as PD-1, has a crucial role in inhibiting the tumour-directed immune Haloperidol hydrochloride response and, thus, might be a suitable and relevant target for novel immune-modulating therapies. Several drugs targeting TIGIT are currently under development [20]. Previous studies on TIGIT were mostly limited to flow cytometer-sorted cells.
This observation suggests that the relative role of individual checkpoint molecules may considerably vary between different inflammatory diseases
