黑料不打烊

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鈥檚 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 黑料不打烊 University Health Centre (RI-MUHC), the Montreal Children's Hospital of the MUHC (MCH-MUHC) and 黑料不打烊 University, in collaboration with French teams from AP-HP, Inserm, Universit茅 Paris-Descartes, Universit茅 Paris-Diderot, 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.

"This study places the TIM-3 protein at the heart of immune system regulation. We could use it as a target in immunotherapies to trigger enhanced immune responses in patients with cancer and better treat them," says co-lead author of this study, Dr. Nada Jabado, who is a researcher from the Child Health and Human Development Program at the RI-MUHC and an hemato-oncologist at MCH-MUHC.

Researchers found that when the TIM-3 protein is suppressed or inactive, the immune system becomes completely 鈥渦nleashed鈥� 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.

These results, which led researchers to consider this form of lymphoma as a new genetic disease, are being published in the journal Nature Genetics on Monday, October 29.

A medical puzzle solved by international cooperation

"It all started here in Montreal with a brother and sister stricken with a rare form of lymphoma, which led to the identification of a much more widespread genetic syndrome across Southeast Asia, Polynesia, Australia and Europe," explains lead author of the study, Tenzin Gayden, a postdoctoral researcher in Dr. Jabado's laboratory at the RI-MUHC.

In the winter of 2016, Dr. David Mitchell and Dr. Sharon Abish, hemato-oncologists at the Montreal Children's Hospital, contacted their colleague Dr. Jabado when one of their 9-year-old patients presented exactly the same symptoms as her younger brother, who was treated a year earlier for LTSCP. The girl had long episodes of fever and began to have edema on the skin.

Suspecting a genetic cause, the team looked into this medical puzzle. Using point of care genetic sequencing technique at the 黑料不打烊 University and G茅nome Qu茅bec Innovation Centre, the researchers discovered that the two sick children carry the same mutation on a gene called HAVCR2, 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. In all, 17 pediatric and adult cases were the subject of this scientific publication.

Beyond rare cases of lymphoma

In most countries of the world, lymphoma cases are treated like cancers, when in reality they are intensified responses of our immune system.

"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 also a professor of Pediatrics and Human genetics at 黑料不打烊 University.

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.

Quotes

"We are pleased that the research results, uncovered by Dr. Jabado and her colleagues, have led to the discovery of a new target for immunotherapy treatments. We have believed in the project since it started and are pleased to have contributed to this major discovery. This news confirms the importance of providing researchers with the necessary funding to advance pediatric research and to bring hope to sick children and their families," explains Jos茅e Saint-Pierre, president and CEO of the Foundation of Stars.

"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," says Dr. Genevi猫ve 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 (co-lead author of the study).

"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 immunosuppressive treatment," explains Dr. David Michonneau from the hematology-transplant service in the Saint-Louis AP-HP hospital and Universit茅 Paris Diderot (co-lead author of the study).

About the study

The study Germline HAVCR2 mutations altering TIM-3 characterize subcutaneous panniculitis- like T cell lymphomas with hemophagocytic lymphohistiocytic syndrome, was co-authored by Tenzin Gayden and Fernando E. Sepulveda (First authors), and by Genevi猫ve De Saint Basile, David Michonneau and Nada Jabado (Lead authors). To access the paper online including the entire list of co-authors

This work was supported a grant from the Fondation des 茅toiles, INSERM, CNRS, l鈥橝P-HP, Universit茅 Paris-Descartes and Coll猫ge de France.

About the Research Institute of the MUHC : The Research Institute of the 黑料不打烊 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 黑料不打烊 University, is the research arm of the 黑料不打烊 University Health Centre (MUHC) 鈥� 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 Qu茅bec 鈥� Sant茅 (FRQS)..

脌 propos de l鈥橝P-HP : L鈥橝P-HP est un centre hospitalier universitaire, acteur majeur de la recherche clinique en France et en Europe mondialement reconnu. Ses 39 h么pitaux accueillent chaque ann茅e 8 millions de personnes malades : en consultation, en urgence, lors d鈥檋ospitalisations programm茅es ou en hospitalisation 脿 domicile. Elle assure un service public de sant茅 pour tous, 24h/24, et c鈥檈st pour elle 脿 la fois un devoir et une fiert茅. L鈥橝P-HP est le premier employeur d鈥櫭巐e-de-France : 100 000 personnes 鈥� m茅decins, chercheurs, param茅dicaux, personnels administratifs et ouvriers 鈥� y travaillent.

脌 propos de l鈥橦么pital universitaire Necker-Enfants malades AP-HP : L鈥檋么pital universitaire Necker-Enfants malades propose l鈥檈nsemble des sp茅cialit茅s m茅dicales et chirurgicales p茅diatriques, un service d鈥檃ccueil des urgences p茅diatriques, une maternit茅 de type 3 et des services adultes tr猫s sp茅cialis茅s (n茅phrologie, transplantation r茅nale, h茅matologie, maladies infectieuses). Il est le si猫ge du SAMU 75, AP-HP. H么pital de recours pour le traitement de pathologies lourdes et complexes, ses 茅quipes ont d茅velopp茅 une approche m茅dicale de haut niveau gr芒ce 脿 la forte synergie entre les unit茅s cliniques, le plateau technique et les unit茅s de recherche qui font de l鈥檋么pital un acteur important de la recherche clinique avec plus de 500 projets en cours. Il abrite pr猫s de 60 centres de r茅f茅rence ou de comp茅tence de maladies rares. Ses 5 000 professionnels prennent en charge plus de 500 000 patients par an, dont pr猫s de 17% viennent de province ou de l鈥櫭﹖ranger.

脌 propos de l鈥橧nserm : L鈥橧nserm est un 茅tablissement public 脿 caract猫re scientifique et technologique, plac茅 sous la double tutelle du minist猫re de la Sant茅 et du minist猫re de la Recherche. D茅di茅 脿 la recherche biologique m茅dicale et 脿 la sant茅 humaine, il se positionne sur l鈥檈nsemble du parcours allant du laboratoire de recherche au lit du patient. Sur la sc猫ne internationale, il est le partenaire des plus grandes institutions engag茅es dans les d茅fis et progr猫s scientifiques de ces domaines.

脌 propos de l鈥橧nstitut Imagine : Premier p么le europ茅en de recherche, de soins et d鈥檈nseignement sur les maladies g茅n茅tiques, l鈥橧nstitut Imagine a pour mission de les comprendre et les gu茅rir. L鈥橧nstitut rassemble 900 des meilleurs m茅decins, chercheurs et personnels de sant茅 dans une architecture cr茅atrice de synergies. C鈥檈st ce continuum in茅dit d鈥檈xpertises, associ茅 脿 la proximit茅 des patients, qui permet 脿 Imagine d鈥檃cc茅l茅rer les d茅couvertes et leurs applications au b茅n茅fice des malades.

脌 propos de l鈥橴niversit茅 Paris Descartes : L鈥橴niversit茅 Paris Descartes, l鈥檜niversit茅 des sciences de l鈥橦omme et de la sant茅 脿 Paris. Avec ses 9 Unit茅s de Formation et de Recherche (UFR) et son IUT, l鈥橴niversit茅 Paris Descartes couvre l鈥檈nsemble des connaissances en sciences de l鈥橦omme et de la sant茅. Seule universit茅 francilienne r茅unissant m茅decine, pharmacie, dentaire et ma茂eutique, son p么le sant茅 est internationalement reconnu pour la qualit茅 de ses formations et l鈥檈xcellence de sa recherche.

Media contact:

Julie Robert
Communications Coordinator 鈥� Research
黑料不打烊 University Health Centre
Cell: 514-971-4747
julie.robert [at] muhc.mcgill.ca