Blood cancers

Prof Miles Prince: genetic studies probe under the skin of rare T-cell lymphoma

Professor Miles Prince

A number of mutations causing T-cell immunoglobulin mucin 3 (TIM-3) alterations have been identified as the causative genetic defects in subcutaneous panniculitis-like T cell lymphoma (SPTCL).

The international research published in Nature Genetics, comprised whole-exome and targeted sequencing on a series of 27 patients with SPTCL. It revealed missense variants in HAVCR2, which encodes TIM-3, in the majority of cases.

The Limbic asked one of the Australian co-authors, Professor Miles Prince from the Peter MacCallum Cancer Centre, about the research and its implications.

How does this study change our thinking about this rare lymphoma?

We have always considered SPTCL as in ‘the grey-zone’ between lymphoma and an autoimmune disease. Indeed, the fact that the best therapy is cyclosporin suggests it is more the latter, and this study supports a corrupt immune system as its cause. Secondly, this is the first lymphoma where we have identified a germline predisposition. This will help us diagnose the condition and also screen relatives. Lastly, it may lead us to research that helps elucidate the aetiology of some forms of hemophagocytic lymphohistiocytosis (HLH).

TIM-3 is described as a negative immune checkpoint and ‘a critical regulator of innate immunity and inflammatory responses’. What do we know about it? 

This molecule, like PD1 is an important regulator. However, it was never really considered as important in HLH or forms of lymphoma.

The research found SPTCL patients with TIM-3 alterations had a younger age of onset and more severe disease including HLH than patients with wild-type TIM-3. How might this finding help in the clinical setting?

At this stage, these are preliminary findings and need confirmation. Moreover, we need to explore if these germline mutations are associated with other forms of lymphoma and/or HLH.

An experimental component to the study suggests immunosuppression and novel agents targeting IL-1 or IFN-γ will be safe and effective in HLH-SPTCL. What have been the clinical outcomes in this disease and can we expect improvements?

Cyclosporin is the cornerstone of treatment for SPTCL but sometimes it is insufficient to manage the HLH. More studies need to be done to see if the presence of the TIM-3 gene (HAVCR2) influences risk of, and responsiveness to therapy in SPTCL.

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