Following the 2018 Nobel Prize for Medicine, global attention is now more than ever turned toward the promise of immunotherapy in oncology. According to a recent study published in the international journal of Nature Genetics, scientists and physicians from the McGill University Health Centre identified a molecule called TIM-3 that might play a key role in the regulation of the immune response. This special molecule is expected to function as the next potential target for immunotherapy treatments in patients with cancers and other diseases.
Researchers found that when the TIM-3 protein is suppressed or inactive, the immune system becomes completely “unleashed” and T cells are uncontrollably over-activated, resulting in subcutaneous panniculitis T lymphoma (LTSCP), a form of cancer that starts in the lymphocytes. The study also shows that the team of researchers has identified two founder mutations at the origin of this syndrome, which acts directly on the TIM-3 protein, preventing it from expressing itself on the surface of the lymphocytes and attacking the cancer cells.
They also found that this form of lymphoma associated with over-activation of the immune response was more widespread than they first thought. Both mutations have been found in individuals of East Asian, Australian, Polynesian and European origin. They also detected the same rare form of lymphoma in these individuals’ brothers and sisters. After sequencing their genomes, the researchers discovered that all of the patients carried the same mutation on a gene called HAVCR2 that codes for TIM-3 and that it was transmitted by their parents.
Thereafter, the team realized they too had similar cases of patients with the same mutation (Tyr82Cys) who seemed to be mostly of East Asian or Polynesian descent. Another mutation (Ile97Met), on the same gene, was identified in patients of European origin. David Michonneau, one of the researchers, stated that the discovery of this mutation has shed light on a previously undescribed mechanism that allowed us to explain both the clinical presentation and the very particular evolution of these lymphomas under treatment.
The results of this study demonstrate the regulatory role of the TIM-3 molecule in humans and they also provide strong arguments for promoting the use of immunosuppressive drugs in the treatment. A researcher of the study Nada Jabado said that for these patients with this rare form of lymphoma, the results of the study reinforce the use of immunosuppressive therapies that will provide much better results and fewer side effects than cytotoxic chemotherapy. Researchers are now trying to see if patients with autoimmune diseases such as lupus may have some TIM-3 dysfunction. There would also be promising avenues for the treatment and understanding of human diseases including cancers and infectious diseases such as HIV.
Tenzin Gayden, Fernando E. Sepulveda, Dong-Anh Khuong-Quang, et al. Germline HAVCR2 mutations altering TIM-3 characterize subcutaneous panniculitis-like T cell lymphomas with hemophagocytic lymphohistiocytic syndrome. Nature Genetics, 2018; DOI: 10.1038/s41588-018-0251-4