Role of common gamma chain-dependent cytokines in the prevention and treatment of relapsing leukemia
Hélène Decaluwe, MD, MSc, PhD, FRCPC
Hélène Decaluwe is a Clinician Scientist working in the area of Pediatric Immunology. The main interests of her laboratory are the role of γc-dependent cytokines in the differentiation of CD8 T cells and their critical importance in the eradication of leukemic and virally infected cells. Her current objectives are a continuation of the work initiated during her PhD training in the excellent laboratory of James Di Santo at Pasteur Institute, Paris (2006-2010). As a MD, PhD, she first completed her medical studies at McGill University (1994-1999). Following this, she continued her post-doctoral training in Pediatrics at University of Montreal (1999-2003). Then, she pursued her Pediatric Clinical Immunology training in the world-renowned Immunology Division of Necker-Enfants Malades Hospital in Paris, under the supervision of Alain Fischer. There, she was involved in the diagnosis, treatment and care of children affected by leukemia or severe immunodeficiency diseases that required hematopoietic stem cell transplantation. The expertise gained at Necker Hospital, where she worked throughout her PhD training (2003-2010), allowed her to be recruited as a Pediatric Immunologist in the Immunology and Rheumatology Division of CHU Sainte-Justine and to join the Hematopoietic Stem Cell Transplantation Team of the Hospital. Furthermore, she was recruited as a Clinician Scientist at the Research Center, where she established a dynamic and functional research team interested in the role of γc-dependent cytokines in CD8 exhaustion and memory T cell differentiation, in close collaboration with the Groupe de Recherche sur la Transplantation et l’Immunologie du Sang de Cordon (GRETISC). The CHU Sainte-Justine Research Center has funded this work through start-up grants and a salary award.
Her novel research subject investigates the role of CD8 T lymphocytes in the prevention and treatment of relapsing leukemia, and the contribution of common gamma chain (γc)-dependent cytokines in this context. In fact, the ability to develop and sustain populations of functional T cells after an antigenic challenge is the basis for vaccination and T cell-based immunotherapies. CD8 T cells are the cornerstones of anti-tumoral immunity and the critical lymphocytes involved in the clearance of transformed cancerous cells. Throughout differentiation, CD8 T cells integrate signals that define their cellular fate and modify their functional capacities. However, despite expanding knowledge on the differentiation of CD8 T cells, it remains unclear how CD8 T cells become programmed into either potent effector cells or long-lasting memory cells. Moreover, understanding the factors involved in CD8 T cell exhaustion in the context of cancer is essential to design new therapeutic strategies to treat these diseases in children. Her laboratory is interested in the role of some γc-dependent cytokines in CD8 T cell memory formation and function. Interleukin (IL)-2, -7, -15 and -21, that signal through the γc receptor chain, are critical for the development of naïve CD8 T cells and influence distinct steps of the CD8 T cell differentiation process. Dr. Decaluwe has previously demonstrated that γc-cytokines sustain the proliferation and differentiation of CD8 effector T cells and are indispensable for the generation of CD8 memory after acute viral infection (Decaluwe et al, PNAS 2010). However, their roles remain to be clarified in situations where antigenic presentation and inflammatory cytokines vary, such as during leukemia or upon anti-tumoral therapeutic vaccination. In these settings, the distinct inflammatory and/or suppressive microenvironment, along with the altered antigenic stimulation, modifies the programming of CD8 T cells and their progression to memory. Since γc-cytokines are pleiotropic factors that play complementary or overlapping roles in the CD8 T cell differentiation process, she hypothesized that a combination of IL-2, IL-15 and IL-21 signals contribute to CD8 T cell exhaustion in the context of cancer and to CD8 T cell function upon therapeutic vaccination.
Dr. Decaluwe thus proposes to study the combined role for IL-2, IL-15 and IL-21 signals in the control of leukemia and their impact on the programming of and the protection by CD8 memory T cells following anti-tumoral vaccination. She hopes that the results of her research will demonstrate the critical role for γc-dependent cytokines in the prevention of severe CD8 T cell exhaustion upon leukemia and will suggest which molecular pathways are involved in this process, opening the door for improved immunotherapeutic protocols during the initial treatment of leukemia or upon its relapse.