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Cell intrinsic control of CD4 T cell differentiation by cytosolic DNA sensing pathways

Periodic Reporting for period 3 - CD4DNASP (Cell intrinsic control of CD4 T cell differentiation by cytosolic DNA sensing pathways)

Reporting period: 2019-08-01 to 2021-01-31

For the last four decades, the treatment of cancer has relied on surgery, radiotherapy, chemotherapy, and hormonotherapy. The therapeutic success of these therapies was solely attributed to their abilities to eliminate tumor cells. This contention was however challenged by me and others showing that optimal therapeutic effects of anticancer therapies require a functional immune system. My team now focuses on the identification of the molecular signals that trigger T cell dependent anticancer immune responses. We specifically investigate how one white blood cell type essential for the development of immune responses, CD4 T cells, could be therapeutically exploited in cancer. Effector CD4 T cells were initially classified into two main subsets, TH1 and TH2 cells. Novel subsets of CD4 T lymphocytes have since then been identified, including IL-9-producing TH9 cells, which mediate potent anticancer activities upon transfer in vivo. However, the mechanisms regulating their growth remain incompletely defined. The aim of my laboratory is thus to enhance the anticancer efficacy of CD4 T cells in mouse and humans to contemplate their use in anticancer adoptive T cell therapy. We found that inside CD4 T cells some molecules specifically involved in the recognition of signals perceived as dangerous for the cells could be targeted to enhance the anticancer effects of T cells. We are investigating the molecular mechanisms underlying these observations to translate this knowledge into a therapeutic strategy against cancer.
We have tested the ability of a molecule that is a danger signal to CD4 T cells to enhance their activity. We found that their activity was indeed enhanced upon activation of molecules recognizing danger signals. We have obtained results explaining how this process occurs inside the CD4 T cells upon activation. Because some danger signals can trigger anticancer immune responses in vivo, we have tested the ability of our candidate molecule to favor anticancer immunity. We found that our candidate molecule triggered anticancer immunity through activation of T cells.
We will investigate further the events triggered by danger signals in T cells to define the signaling pathways involved and exploit this knowledge for anticancer immunotherapy.