Summary: T cell immunoglobulin and ITIM domain (TIGIT) is an inhibitory receptor expressed on lymphocytes that was recently propelled under the spotlight as a major emerging target in cancer immunotherapy. TIGIT interacts with CD155 expressed on antigen-presenting cells or tumour cells to down-regulate T cell and natural killer (NK) cell functions. TIGIT has emerged as a key inhibitor of anti-tumour responses that can hinder multiple steps of the cancer immunity cycle. Pre-clinical studies indicated that TIGIT blockade may protect against various solid and haematological cancers. Several monoclonal antibodies (mAbs) that block the inhibitory activity of human TIGIT have been developed. Clinical trials are ongoing, investigating TIGIT blockade as a monotherapy or in combination with anti-PD1/PD-L1 mAbs for the treatment of patients with advanced solid malignancies. In this review, we cover our current knowledge on TIGIT, from its discovery in 2009 to its current status as a clinical target.

Immune-based therapies hold promise for the treatment of multiple myeloma (MM), but so far immune checkpoint blockade targeting programmed cell death protein 1 (PD-1) has not proven effective as single agent in this disease. T cell immunoglobulin and ITIM domains (TIGIT) is another immune checkpoint receptor known to negatively regulate T cell functions. In this study, we investigated the therapeutic potential of TIGIT blockade to unleash immune responses against MM. We observed that, in both mice and humans, MM progression was associated with high levels of TIGIT expression on CD8⁺ T cells. TIGIT⁺ CD8⁺ T cells from MM patients exhibited a dysfunctional phenotype, characterized by decreased proliferation and inability to produce cytokines in response to anti-CD3/CD28/CD2 or myeloma antigen stimulation. Moreover, when challenged with Vk*MYC mouse MM cells, TIGIT-deficient mice showed decreased serum M-protein levels associated with reduced tumor burden and prolonged survival, indicating that TIGIT limits anti-myeloma immune responses. Importantly, blocking TIGIT using monoclonal antibodies (mAbs) increased the effector function of MM patient CD8⁺ T cells and suppressed MM development. Altogether our data provide evidence for an immune-inhibitory role of TIGIT in MM and support the development of TIGIT-blocking strategies for the treatment of MM patients. Key points TIGIT expression is up-regulated on CD8⁺ T cells during MM progression and is associated with impaired effector functions. TIGIT-deficiency or -blockade protects mice against multiple myeloma and improves effector functions of myeloma patient CD8⁺ T cells.

Autologous stem cell transplantation (auto-SCT) remains a standard of care for multiple myeloma patients and prolongs progression-free survival. A small cohort of patients achieve long-term control of disease, however the majority of patients ultimately relapse, and the mechanisms permitting disease progression remain unclear. In this study, we used a preclinical model of autologous SCT for myeloma where the disease either progressed (MM-relapsed) or was controlled. In the bone marrow (BM), inhibitory receptor expression on CD8⁺ T-cells correlated strongly with myeloma progression after transplant. In conjunction, the co-stimulatory/adhesion receptor CD226 (DNAM-1) was markedly downregulated. Interestingly, DNAM-1^- CD8⁺ T-cells in MM-relapsed mice had an exhausted phenotype, characterized by upregulation of multiple inhibitory receptors, including immunoglobulin and ITIM domains (TIGIT), programmed death 1 (PD-1) with decreased T-bet and increased Eomesodermin expression. Immune checkpoint blockade using monoclonal antibodies against PD-1 or TIGIT significantly prolonged myeloma control after SCT. Furthermore, CD8⁺ T-cells from MM-relapsed mice exhibited high interleukin-10 (IL-10) secretion that was associated with increased TIGIT and PD-1 expression. However, while donor-derived IL-10 inhibited myeloma control post-SCT, this was independent of IL-10 secretion by, or signaling to T-cells. Instead, the donor myeloid compartment, including CSF-1R-dependent macrophages and an IL-10-secreting dendritic cell population in the BM, promoted myeloma progression. Our findings highlight PD-1 or TIGIT blockade in conjunction with SCT as a potent combination therapy in the treatment of myeloma. Key points Myeloma promotes CD8⁺ T-cell exhaustion and IL-10 secretion from dendritic cells. PD-1 and TIGIT-targeted checkpoint inhibition is effective after SCT.