TIGIT: a potential target for checkpoint inhibition in multiple myeloma

Checkpoint inhibitors, such as monoclonal antibodies that specifically block the action of programmed cell death protein 1 (PD-1) or its ligand, PD-L1, are very promising immunotherapy tools that can evoke strong anti-tumor immune responses. At present, checkpoint inhibitors are being tested in the pre-clinical and clinical trial setting for their efficacy in treating multiple myeloma (MM).

In this study, Camille Guillerey and Heidi Harjunpää, both from the School of Medicine, University of Queensland, Herston, Australia, and collaborators, investigated the potential of TIGIT (T cell immunoglobulin and ITIM domains), an inhibitory lymphocyte receptor, as a potential target for checkpoint inhibition in MM. The study was published in the journal Blood in July 2018.

Key Data:

TIGIT expression becomes higher as the MM progresses and correlates with defective T cell effector functions

• TIGIT expression was analyzed with flow cytometry to study the pattern of expression in MM cells
  • TIGIT expression was undetectable in naïve mice but detected at high levels after mice were challenged with an intravenous (IV) injection of a MM cell line; the percentages of TIGIT+ CD8+ T cells increased with time post-IV, as the disease progressed
  • Higher levels of TIGIT were observed in bone marrow (BM) CD8+ T cells from newly diagnosed or relapsed MM patients than in healthy donors
  • TIGIT was more often expressed in MM patient CD8+ T cells compared to other immunotherapy targets such as PD-1, TIM-3, LAG-3, and CTLA-4
• To compare the effector functions of TIGIT+ and TIGIT- CD8+ T cells, MM BM CD138- cells were stimulated with anti-CD3/CD28/CD2 microbeads followed by flow cytometry
  • Both T cell subsets were activated, shown by CD69 expression
  • TIGIT CD8+ T cells produced minute amounts of cytokines (TNFα and IFNγ) and low CD107a expression, a marker of natural killer (NK) cell activity
  • TIGIT CD8+ T cells exhibited low proliferative capacity, evaluated with Cell Trace Violet (CTV) staining, indicating that this cell type had fully differentiated

Blocking TIGIT protects mice from developing MM and improves MM patient CD8+ T cell effector functions

• To understand the role of TIGIT in MM pathogenesis in vivo, wild type and knockout mice for Tigit (Tigit^-/- mice) were challenged with an IV injection of a MM cell line
  • Paraprotein levels were higher in the serum of wild type mice compared to those in Tigit^-/- mice six weeks after the injection
  • Survival was significantly better in Tigit^-/- mice compared to controls over a period of 120 days
• To decipher whether CD8+ T cells were involved in protecting Tigit^-/- mice against MM, wild type and knockout mice for Tigit (Tigit^-/- mice) were challenged with an IV injection of a MM cell line as well as intraperitoneal injections of an anti-CD8 antibody to abolish function of CD8+ T cells
  • High paraprotein levels were observed in the serum, spleen, and BM four weeks after IV injection in both wild type and Tigit^-/-
• To investigate the therapeutic potential of blocking TIGIT function, anti-TIGIT antibodies were injected in wild type mice inoculated with a MM cell line
  • Paraprotein levels were reduced in the serum and BM of these mice
  • The survival of these mice was extended
  • Anti-TIGIT treatment was more effective compared to anti-PD1 treatment in these mice
• Treating MM patient CD8+ cells with anti-TIGIT antibodies, improved cytokine production and degranulation

Conclusions

This study supports TIGIT as an important molecule in the inhibitory checkpoint pathway in MM both in pre-clinical MM models as well as in CD8+ T cells from MM patients. This provides the basis for further investigating the use of anti-TIGIT antibodies as checkpoint inhibitors for MM.