Rosalind and Morris
Goodman Cancer
Institute Principal
Investigators
Prof. Heather Melichar's lab focuses on:
- The T cell receptor signals that support the development and function of T cells;
- The identification of factors that modulate the anti-tumour T cell response;
- The mechanisms that ensure T cell tolerance/prevent autoimmunity.
T cells are an important component of the immune system. They play an essential role in fighting infections and cancer, but, unfortunately, they can also contribute to the development of several autoimmune diseases. Thus, there are stringent regulatory processes in place that accompany T cell development in the thymus as well as additional checkpoints that control mature T cell function. Dr. Melichar is interested in the mechanisms that maintain a functional and safe population of T cells. The focus of the research program is on the regulators of T cell activity and has important clinical implications. The team uses knowledge gained from these studies to develop new therapeutic discovery platforms and drugs to treat cancer.
What we are
currently
working on
In order to recognize diseased and infected cells, T cells require a diverse repertoire of antigen receptors that must distinguish, with exquisite specificity, foreign and mutated antigens from normal self-peptides. Antigen receptor diversity is generated during T cell development in the thymus. Within the thymus, rigorous selection processes accompany T cell differentiation to ensure the functionality and self-tolerance of the unique antigen receptors expressed on individual T cells. Once mature T cells leave the thymus, they encounter a battery of additional checkpoints that regulate their activation in the peripheral lymphoid organs. In addition to their natural role in eliminating abnormal and infected cells, the anti-tumour potential of T cells is being harnessed and re-wired to develop powerful new immunotherapies. Our research program addresses fundamental and translational aspects of T cell development and function. For these studies, we use an array of high-content approaches that allow us to maintain, manipulate, and probe the intact 3-dimensional space of lymphoid tissues. This includes time-lapse imaging of cells in vitro and in situ, mouse and human organotypic culture, genetically engineered mouse models, transcriptome analyses, and multiparametric flow cytometry.
- Éducation des cellules T dans le thymus L’énorme diversité des spécificités du récepteur de cellule T requise pour reconnaître n’importe quel peptide étranger ou muté pouvant être rencontré durant la vie d’un individu est généré lors du développement des cellules T dans le thymus. Une possibilité de 1020 récepteurs de cellules T différents peuvent être produits, mais ce ne sont pas tous les événements de recombinaison des gènes du récepteur de cellules T qui sont appropriées. Nous cherchons à comprendre comment la signalisation par le récepteur de cellule T assure la génération d’un répertoire de cellules T fonctionnel et tolérant au soi, et aussi comment les interactions entre les cellules T et leur environnement influence ultimement la qualité de la réponse des cellules T aux infection ou au cancer. T cell education in the thymus The enormous diversity of T cell receptor specificities that are required to recognize any foreign or mutated peptide that may be encountered throughout a lifetime is generated during T cell development in the thymus. A possible 1020 different T cell receptors can be produced, but not all T cell receptor gene recombination events are appropriate. We are working to understand how signals through the T cell receptor ensure the generation of a functional, self-tolerant T cell repertoire and also how the interactions between T cells and their environment ultimately influence the quality of the T cell response to infection or cancer.
- Modulation des points de contrôles de la fonction des cellules T La fonction des cellules T est modulée positivement et négativement par des molécules de cosignalisation appartenant aux superfamilles des immunoglobulines et des récepteurs de facteurs de nécrose tumorale qui sont devenues d’importantes cibles thérapeutiques. La manipulation de ces molécules de point de contrôle pour revigorer la réponse anti-tumorale des cellules T a significativement prolongé la vie de plusieurs patients atteints de cancer. Par contre, un nombre substantiel de patients recevant ces immunothérapies ne répondent pas à ces traitements. Nous nous intéressons à définir la fonction immunorégulatrice de certains récepteurs orphelins de la superfamille des récepteurs de facteurs de nécrose tumorale pour identifier des cibles additionnelles dans l’axe de cosignalisation des cellules T afin de traiter avec succès un plus grand éventail de patients. Checkpoint modulation of T cell function T cell function is positively and negatively modulated by co-signaling molecules that belong to the immunoglobulin and tumour necrosis factor receptor superfamilies that have become important therapeutic targets. Manipulation of these checkpoint molecules to invigorate the anti-tumour T cell response has significantly extended the lives of many cancer patients. However, a substantial number of patients receiving these immunotherapies fail to respond. We are interested in defining the immunoregulatory function of orphan tumour necrosis factor receptor superfamily members to identify additional targets within the T cell co-signaling axis to successfully treat a wider range of patients.
- Prédire le destin des cellules T La liaison d’un récepteur de cellule T à un antigène mène à une cascade rapide d’événements de signalisation qui incluent une augmentation du calcium intracellulaire. Les différences dans les niveaux de calcium peuvent mener à différent résultats transcriptionnels. La stimulation du récepteur de cellules T induit des changements dans la concentration de calcium intracellulaire avec une dynamique temporelle qui contient de l’information à propos de l’affinité du récepteur de cellule T pour l’antigène apparenté. Nous utilisons des analyses d’apprentissage automatisé d’images prises à intervalles réguliers des dynamiques de calcium dans les cellules T en développement et matures pour prédire les destins développementaux et fonctionnels. Predicting T cell fate Binding of a T cell receptor to antigen leads to a rapid cascade of signaling events that includes increases in intracellular calcium. Differences in calcium levels can lead to distinct transcriptional outcomes. T cell receptor stimulation induces changes in intracellular calcium concentration with temporal dynamics that contain information about T cell receptor affinity for cognate antigen. We are using machine learning analysis of time-lapse imagines of calcium dynamics in developing and mature T cells to predict developmental and functional outcomes.
- Member, Rosalind and Morris Goodman Cancer Institute (2023-present)
- Associate Professor, Department of Microbiology and Immunology (2023-present)
- Associate Member, Department of Physiology (2023-present)
- Governing Council Member, Canadian Society for Immunology (2019-2023)
- FRQS Senior (2022-2026)
- FRQS Junior 2 (2020-2022)
- CIHR New Investigator (2015-2020)
- FRQS Junior 1 (2014-2018)
Our team
Ève Mallet Gauthier Étudiant.e au doctorat PhD Student 
Marilaine Fournier Associé.e de recherche Research Associate 
Ryan LaFrancois Étudiant.e à la maîtrise MSc Student 
Sébastien This Candidat.e postdoctoral.e Postdoctoral Fellow 
Stefanie Valbon Étudiant.e au doctorat PhD Student
Major discoveries
- 2007 Identification of Sox13 as an important regulator of gamma-delta T cell development.
- 2013 Development of a human thymic slice organ culture platform.
- 2013 In situ imaging of T cell receptor signals that accompany T cell development.
- 2017 Thymic imprinting of T cell effector function in neonates and adults.
- 2019 T helper biases in naive T cells prior to activation.
- 2020 Development of new model systems to parse the mechanisms of T cell tolerance.
- 2021 CD5 levels identify functionally heterogeneous human T cell populations.
- 2023 Vitamin D is a coactivator of an essential T cell tolerance factor.
- 2023 Machine learning algorithms to predict T cell antigen-specificity based on intracellular calcium fluctuations.
Research Partners
Get in touch
3655 Promenade Sir William Osler
Montreal, Quebec H3G 1Y6
Office: 713A
Lab: 713
T. 514-398-1761
T.
F.
heather.melichar@mcgill.ca
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