Scientific breakthrough: Promising new target for immunotherapy

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Credit: McGill University Health Centre

An international team identifies a key molecule in immune system regulation linked to new genetic disease

Following the 2018 Nobel Prize for Medicine, global attention is now more than ever turned toward the promise of immunotherapy in oncology. An international team's work has shed new light on a molecule called TIM-3 that might play a key role in the regulation of the immune response.

Scientists and physicians from the Research Institute of the McGill University Health Centre (RI-MUHC), the Montreal Children's Hospital of the MUHC (MCH-MUHC), and McGill University in collaboration with French teams from AP-HP, Inserm, Université Paris-Descartes and the Imagine Institute at the Necker-Enfants Malades Hospital, have singled out this protein as the next potential target for immunotherapy treatments in patients with cancer and other diseases.

These results are being published in the journal Nature Genetics on Monday, October 29.

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 a rare form of lymphoma (a form of cancer that starts in the lymphocytes) called subcutaneous panniculitis T lymphoma (LTSCP).

The team of researchers has identified two founder mutations at the origin of this syndrome, which act 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, and Polynesian origin as well as in patients of European origin.

This work was based on findings from the teams at the RI-MUHC and the MCH-MUHC, showing the same rare form of lymphoma in brother and sister. After sequencing their genomes, the researchers discovered that both patients carried the same mutation on a gene called HAVCR2 that codes for TIM-3 and that it was transmitted by their parents.

In discussions with colleagues in Australia and France, 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. A functional study of these mutations, conducted in Paris, confirms their responsibility in this new genetic disease. In all, 17 pediatric and adult cases were the subject of this scientific publication.

"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," explains Dr. David Michonneau from the hematology-transplant service in the Saint-Louis AP-HP hospital.

According to Dr. Geneviève de Saint Basile from the laboratory "Molecular basis of immune homeostasis abnormalities" Inserm at the Imagine Institute and the center for the study of immunodeficiencies at Necker-Children's Hospital AP-HP, "The results of this collaboration demonstrate the regulatory role of the TIM-3 molecule in humans and they also provide strong arguments for reconsidering this entity as an inflammatory rather than a malignant pathology, and for promoting the use of immunosuppressive drugs in its treatment."

"For these patients with this rare form of lymphoma, our results reinforce the use of immunosuppressive therapies that will provide much better results and fewer side effects than cytotoxic chemotherapy," says Dr. Nada Jabado, who is a clinician-scientist from the Child Health and Human Development Program at the RI-MUHC and a professor of Pediatrics and Human Genetics at McGill University in Montreal.

Researchers are now trying to see if patients with autoimmune diseases such as lupus – a disease where the immune system turns against the body itself – may have some TIM-3 dysfunction. There would also be promising avenues for the treatment and understanding of cancers, infectious diseases such as HIV or even malaria as well as multiple sclerosis.

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This work was supported by a grant from the Fondation des étoiles, INSERM, CNRS, l'AP-HP, Université Paris-Descartes and Collège de France.

Source:

Germline HAVCR2 mutations altering TIM 3 characterize subcutaneous panniculitislike T cell lymphomas with hemophagocytic lymphohistiocytic syndrome Tenzin Gayden 1,31, Fernando E. Sepulveda 2,31, Dong-Anh Khuong-Quang 3,4,31, Jonathan Pratt1,31, Elvis T. Valera 1,5, Alexandrine Garrigue2, Susan Kelso6,7, Frank Sicheri6,7, Leonie G. Mikael1, Nancy Hamel8, Andrea Bajic 1, Rola Dali9, Shriya Deshmukh10, Dzana Dervovic6, Daniel Schramek6,7, Frédéric Guerin2, Mikko Taipale7, Hamid Nikbakht 1,9, Jacek Majewski 1,11, Despina Moshous 12, Janie Charlebois13, Sharon Abish13, Christine Bole-Feysot14, Patrick Nitschke 15, Brigitte Bader-Meunier12, David Mitchell13, Catherine Thieblemont16,17, Maxime Battistella17,18, Simon Gravel11, Van-Hung Nguyen19, Rachel Conyers3,4, Jean-Sebastien Diana12, Chris McCormack20,21, H. Miles Prince22, Marianne Besnard23, Stephane Blanche12, Paul G. Ekert 3,4, Sylvie Fraitag24, William D. Foulkes 1,8, Alain Fischer12,25,26, Bénédicte Neven12,26,32, David Michonneau 17,27,32, Geneviève de Saint Basile 2,28,32* and Nada Jabado 1,29,30,32*

About the Research Institute of the MUHC : The Research Institute of the McGill University Health Centre (RI-MUHC) is a world-renowned biomedical and healthcare research centre. The Institute, which is affiliated with the Faculty of Medicine of McGill University, is the research arm of the McGill University Health Centre (MUHC) – an academic health centre located in Montreal, Canada, that has a mandate to focus on complex care within its community. The RI-MUHC supports over 420 researchers and close to 1,200 research trainees devoted to a broad spectrum of fundamental, clinical and health outcomes research at the Glen and the Montreal General Hospital sites of the MUHC. Its research facilities offer a dynamic multidisciplinary environment that fosters collaboration and leverages discovery aimed at improving the health of individual patients across their lifespan. The RI-MUHC is supported in part by the Fonds de recherche du Québec – Santé (FRQS). http://www.rimuhc.ca

À propos de l'AP-HP : L'AP-HP est un centre hospitalier universitaire, acteur majeur de la recherche clinique en France et en Europe mondialement reconnu. Ses 39 hôpitaux accueillent chaque année 8 millions de personnes malades : en consultation, en urgence, lors d'hospitalisations programmées ou en hospitalisation à domicile. Elle assure un service public de santé pour tous, 24h/24, et c'est pour elle à la fois un devoir et une fierté. L'AP-HP est le premier employeur d'Île-de-France : 100 000 personnes – médecins, chercheurs, paramédicaux, personnels administratifs et ouvriers – y travaillent. http://www.aphp.fr

À propos de l'Hôpital universitaire Necker-Enfants malades AP-HP : L'hôpital universitaire Necker-Enfants malades propose l'ensemble des spécialités médicales et chirurgicales pédiatriques, un service d'accueil des urgences pédiatriques, une maternité de type 3 et des services adultes très spécialisés (néphrologie, transplantation rénale, hématologie, maladies infectieuses). Il est le siège du SAMU 75, AP-HP. Hôpital de recours pour le traitement de pathologies lourdes et complexes, ses équipes ont développé une approche médicale de haut niveau grâce à la forte synergie entre les unités cliniques, le plateau technique et les unités de recherche qui font de l'hôpital un acteur important de la recherche clinique avec plus de 500 projets en cours. Il abrite près de 60 centres de référence ou de compétence de maladies rares. Ses 5 000 professionnels prennent en charge plus de 500 000 patients par an, dont près de 17% viennent de province ou de l'étranger.

À propos de l'Inserm : L'Inserm est un établissement public à caractère scientifique et technologique, placé sous la double tutelle du ministère de la Santé et du ministère de la Recherche. Dédié à la recherche biologique médicale et à la santé humaine, il se positionne sur l'ensemble du parcours allant du laboratoire de recherche au lit du patient. Sur la scène internationale, il est le partenaire des plus grandes institutions engagées dans les défis et progrès scientifiques de ces domaines.

À propos de l'Institut Imagine : Premier pôle européen de recherche, de soins et d'enseignement sur les maladies génétiques, l'Institut Imagine a pour mission de les comprendre et les guérir. L'Institut rassemble 900 des meilleurs médecins, chercheurs et personnels de santé dans une architecture créatrice de synergies. C'est ce continuum inédit d'expertises, associé à la proximité des patients, qui permet à Imagine d'accélérer les découvertes et leurs applications au bénéfice des malades. http://www.institutimagine.org

À propos de l'Université Paris Descartes : L'Université Paris Descartes, l'université des sciences de l'Homme et de la santé à Paris. Avec ses 9 Unités de Formation et de Recherche (UFR) et son IUT, l'Université Paris Descartes couvre l'ensemble des connaissances en sciences de l'Homme et de la santé. Seule université francilienne réunissant médecine, pharmacie, dentaire et maïeutique, son pôle santé est internationalement reconnu pour la qualité de ses formations et l'excellence de sa recherche

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