Blockade of TIGIT/CD155 Signaling Reverses T-cell Exhaustion and Enhances Antitumor Capability in Head and Neck Squamous Cell Carcinoma

Abstract

Immunosuppression is common in head and neck squamous cell carcinoma (HNSCC). In previous studies, the TIGIT/CD155 pathway was identified as an immunecheckpoint signaling pathway that contributes to the "exhaustion" state of infiltrating T cells. Here, we sought to explore the clinical significance of TIGIT/CD155 signaling in HNSCC and identify the therapeutic effect of the TIGIT/CD155 pathway in a transgenic mouse model. TIGIT was overexpressed on tumor-infiltrating CD8 þ and CD4 þ T cells in both HNSCC patients and mouse models, and was correlated with immune-checkpoint molecules (PD-1, TIM-3, and LAG-3). TIGIT was also expressed on murine regulatory T cells (Treg) and correlated with immune suppression. Using a human HNSCC tissue microarray, we found that CD155 was expressed in tumor and tumor-infiltrating stromal cells, and also indicated poor overall survival.Multispectral IHC indicated that CD155 was coexpressed with CD11b or CD11c in tumor-infiltrating stromal cells. Anti-TIGIT treatment significantly delayed tumor growth in transgenic HNSCC mouse models and enhanced antitumor immune responses by activating CD8 þ T-cell effector function and reducing the population of Tregs. In vitro coculture studies showed that anti-TIGIT treatment significantly abrogated the immunosuppressive capacity of myeloid-derived suppressor cells (MDSC), by decreasing Arg1 transcripts, and Tregs, by reducing TGFb1 secretion. In vivo depletion studies showed that the therapeutic efficacy by anti-TIGIT mainly relies on CD8 þ T cells and Tregs. Blocking PD-1/PD-L1 signaling increased the expression of TIGIT on Tregs. These results present a translatable method to improve antitumor immune responses by targeting TIGIT/CD155 signaling in HNSCC.

Heterogeneity of MSI-H gastric cancer identifies a subtype with worse survival

“…Nevertheless, the majority of patients still progress even though tumour response was observed early in ICB antitumor therapy, suggesting that some other immunosuppressors and/or pathways complement the inactivation of PD-1 and CTLA-4. Recently, TIM339 and TIGIT40 have been shown to contribute to T-cell exhaustion, and co-blockade of two pathways (PD-1 and TIM3 or PD-1 and TIGIT) is more effective in restoring T cell proliferation and cytokine production 41–43. Here, we found that in addition to PD-L1/PD-L2 and CTLA-4, TIM3 and TIGIT also had much higher expression levels in the MSI-H1 subgroup (figure 4B).…”

The yin and yang of co-inhibitory receptors: toward anti-tumor immunity without autoimmunity

“…[197][198][199][200] Currently, a number of clinical studies are investigating the therapeutic impact of TIGIT blockade either alone or in combination with PD-1 in multiple cancer types. 196,201,202 The checkpoint receptor LAG-3 holds great potential in cancer immunotherapy. LAG-3 is expressed widely in tumor-infiltrating lymphocytes in various tumors.…”

Tumor immune microenvironment in head and neck cancers

“…While peritumoral CD8 + TILs may indicate an adaptive immune response, studies have shown that dysfunctional TILs are commonly present, which exhibit decreased cytokine production and proliferation ability and lack of cytotoxic functions 24,25 . Exhausted and dysfunctional TILs in HNSCC cases have been characterized by the upregulation of several checkpoint markers, such as programmed cell death 1 (PD‐1), lymphocyte‐activation gene 3 (LAG‐3), T cell immunoglobulin mucin protein‐3 (TIM‐3), cytotoxic T lymphocyte–associated protein 4 (CTLA‐4), and 2B4 26–29 (Figure 1). The cause and mechanisms by which the T cells become exhausted and dysfunctional in HNSCCs are discussed in detail below.…”