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What the TIGIT immune brake reveals in myeloma and other blood cancers

Myeloma studies found that blocking TIGIT improved immune-cell activity in lab tests, while only some bone-marrow samples responded.

Review or Meta-AnalysisMilestone UpdateBy ioQuanta Research Desk · Published ·
TIGIT on an immune cell binds CD155 or CD112 on a nearby cell.

Evidence date · 2021-06-01 · Research note 2 of 3
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Since the previous research note: What does CD155 do to tumor cells and immune cells, and where might TIGIT blockade fit?

Previous expectation: TIGIT blockade might offer another treatment route for advanced solid tumors if it safely improved immune activity and patient outcomes.

What this study adds: The June 2021 review shifts attention to TIGIT in blood cancers, with separately identified earlier studies adding myeloma and myelodysplastic-syndrome observations. It does not test the earlier solid-tumor treatment forecast.

What changed in this study

A receptor found on immune cells can attract attention in cancer for two very different reasons: it may be more common on cells from people with the disease, or interrupting its activity may restore an antitumor response. Research on TIGIT in blood cancers has raised both questions. The distinction matters because a change in immune-cell activity, a result in mice and a benefit for patients are separate kinds of evidence.

A June 2021 review describes TIGIT as an inhibitory receptor on T cells and natural killer cells, two types of immune cell involved in recognizing and responding to abnormal cells. TIGIT can bind to proteins called CD155 and CD112 on other cells. The proposed mechanism is that these interactions help restrain immune activity. The review surveys work on TIGIT in lymphoma, multiple myeloma, leukemia and myelodysplastic syndrome, a group of disorders affecting blood-forming cells.

The breadth of that survey is a reason to pay attention, but it does not mean the evidence is equally detailed across all four diseases. The supplied studies give a closer view of questions in myeloma and myelodysplastic syndrome.

In myeloma, cell activity and tumor outcomes tell different parts of the story

Multiple myeloma develops from malignant plasma cells, which produce antibodies. In a 2018 study, researchers found that TIGIT-positive CD8 T cells from people with myeloma were dysfunctional in laboratory tests. These cells showed reduced proliferation and could not produce cytokines, signaling proteins involved in immune responses, when stimulated by immune signals or myeloma antigens.

That patient-cell finding speaks to function, rather than simply counting how many cells carry TIGIT. It shows that TIGIT-positive cells in the samples had impaired responses under the conditions tested. It does not by itself show what would happen if a patient received a TIGIT-blocking drug.

The study asked a separate intervention question in mice. Mice lacking TIGIT had lower levels of a blood protein associated with myeloma, less tumor burden and longer survival when challenged with myeloma cells. The researchers also reported that antibodies blocking TIGIT increased the activity of patient CD8 T cells in laboratory tests and suppressed myeloma development in experimental settings.

The mouse result adds evidence that TIGIT can constrain antimyeloma activity in that model. It remains distinct from the observations in patient cells: a mouse outcome is not a patient treatment outcome, and a laboratory response in human cells does not establish clinical benefit.

Bone-marrow context may help explain uneven responses

A 2020 myeloma study examined TIGIT and its binding partners in bone marrow, where malignant plasma cells and immune cells are found together. The researchers tested whether the local mix of cells and ligand proteins could help explain why experimental responses to TIGIT blockade varied.

The study found high levels of TIGIT and its ligands in bone-marrow samples from people with myeloma. In laboratory assays, the TIGIT ligand PVR inhibited CD8 T-cell signaling and proliferation, effects that could be overcome with an anti-TIGIT antibody. The researchers also found that bone-marrow immune profiles varied substantially across samples. In functional tests using patient bone-marrow cells, only some samples responded to checkpoint blockade.

Experimental response was associated with two features: lower frequency of TIGIT-positive cells and higher expression of another TIGIT ligand, nectin-2, on malignant plasma cells. These associations point to a more specific question than whether TIGIT is present: the surrounding bone-marrow environment and the distribution of its binding partners may matter when testing blockade. The findings suggest possible markers for studying variation, but they do not establish a way to select patients who would benefit from treatment.

A separate patient-sample question in myelodysplastic syndrome

In myelodysplastic syndrome, an independent 2020 study measured TIGIT on natural killer and T cells in blood samples from patients. Higher TIGIT expression was associated with disease progression and immune escape, alongside lower immune-cell function and reduced release of activation factors. In laboratory tests, blocking TIGIT enhanced the antitumor effects of these cells.

This work adds a different disease-specific observation to the review’s wider scope. It concerns immune cells in patient samples and their activity in tests, rather than the myeloma bone-marrow pattern or the mouse challenge. The review also covers leukemia and lymphoma, but the evidence described here does not support detailed comparisons or conclusions about treatment in those cancers.

What the evidence can and cannot tell us

The June 2021 review abstract surveys TIGIT’s inhibitory role and research across several blood cancers. The supporting studies ask narrower questions: how patient-derived immune cells function, whether blocking TIGIT changes activity in laboratory assays, how bone-marrow ligands relate to experimental responses, and what happens in a mouse myeloma challenge. Each adds a different piece of evidence; none is equivalent to a clinical test of treatment.

Taken as a whole, these findings make TIGIT a plausible target for further investigation in blood cancers. They do not establish that blocking TIGIT safely improves outcomes for patients with myeloma, myelodysplastic syndrome, leukemia or lymphoma. The supplied evidence includes no basis for claiming comparative clinical efficacy or safety. Increased receptor expression alone is not enough to show that a treatment will work.

What TIGIT blockade could change for blood cancers

If blocking TIGIT can restore useful antitumor activity safely and improve outcomes in patients, it could become a treatment approach for some blood cancers. The current findings make that possibility concrete by showing impaired patient-cell responses, changes in experimental assays and an effect in a mouse myeloma model. The step that would give this approach a place in patient care remains demonstrating that the immune activity observed in these settings can translate into safe, meaningful clinical benefit.

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