Etienne Gagnon’s team seeks to decipher the molecular mechanisms that result in certain tumors preventing the immune system from functioning correctly. T lymphocytes are at the heart of his work.
Etienne Gagnon’s work, carried out in Michel Desjardin’s laboratory, made it possible to understand in detail the mechanisms underlying the capacity of macrophages to phagocytize foreign particles, such as bacteria, without overloading the use of their plasma membrane. This discovery enabled the development and validation of a hypothesis involving the mechanisms of antigen cross-presentation, mechanism through which antigens from exogenous pathogens are presented according to an antigen pathway used for the presentation of endogenous antigens.
The work that he carried out at Dana-Farber Cancer Institute made it possible to better understand the mechanisms involved in the activation of T cells and to propose a new regulation model through electrostatic interactions between cytoplasmic domains of TCR accessory chains (CD3e and CD3z) and anionic lipids of the plasma membrane.
To fight infectious diseases, the body uses two immune mechanisms, one innate and one adaptive, that communicate with each other through specialized lymphocytes called “T cells”.
Each T cell has the ability to recognize a specific antigen with high affinity. When a T cell meets its antigen, it activates itself and sets off a cascade of reactions in the body. Like an orchestra conductor, it modulates the activity of a series of immune cells. It succeeds in two ways: by directly associating itself with the effector cells or by releasing proteins called cytokines around it.
But cancer perturbs the activation mechanisms of immunity. It creates background noise that prevents the T cells from uncovering, amongst all the antigens, the ones for which they should normally have sounded the alarm. The tumor microenvironment, rich in cytokines, also contributes to harming the activation of T cells.
In such a context, certain T cells are activated by low affinity liaisons with antigens derived from cancer cells, thus generating immune responses that are not optimal and add to the background noise. A form of immune tolerance then sets in and the immune system becomes less effective in stopping real infections.
Though we understand the effect of the tumor environment on the immune response, the same cannot be said for the molecular mechanisms involved.
The goal of Etienne Gagnon’s team is built around two concepts: thoroughly understanding the molecular basis for the activation of T cells through the TCR, and characterizing the molecular effects of the tumor microenvironment on the cancer cell and the recognition of antigens by T cells.
The Investigators use advanced microscopy techniques, such as the FRET and the FLIM, as well as genetic manipulation and various mouse models to accomplish the task. Through those approaches, they are trying to modify the T cells in order for them to overcome the tolerising effects of cancer.
The team also focuses part of its work on developing new protein architectures to improve the productivity and safety of chimeric antigen receptors (CAR), an immunotherapeutic approach to fight cancer.