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 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 different tumour entities with considerable high variability 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.
Highlights
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 [1,2,3]
Multiplex immunofluorescence analysis of TIGT on CD20+ B lymphocytes, CD3+ T lymphocytes, various T cell subtypes (CD4+, CD8+, FOXP3+; Figures 1(a)–1(c)), CD56+ natural killer cells (Figure 1(d)), CD11c+ dendritic cells (Figure 1(e)), and CD68+ macrophages (Figure 1(f)) revealed that T cell immunoglobulin and ITIM domain (TIGIT) expression is most frequently detected in T lymphocytes and in a subset of NK-cells
52% of CD3+ T cells were TIGIT positive, while no unequivocal staining was seen in CD20+ lymphocytes
Summary
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 [1,2,3]. 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 response and, might be a suitable and relevant target for novel immune-modulating therapies. Several drugs targeting TIGIT are currently under development [20]
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