CV Science

Marie-Cecile Michallet CRCN CNRS scientist

Course and current status

I am an onco-immunologist. I started my carreer in 1999 in Pr J.P. Revillard's lab (Ecole Normale Supérieure de Lyon, France) working on high dose tolerance mechanisms of anti-CD3 antibodies (J Immunol) and Thymoglobulin (Blood), an immunosuppressive drug widely used in transplantation. I then moved to Pr J. Tschopp's lab (Switzerland) as an EMBO post-doctoral fellow. I identified a novel role of the TRADD protein in innate immune responses such as RIG-like helicases (Immunity) and TLRs (Nat Immunol) pathways. I went back in France and got a position as CR1 CNRS in Dr J. Marvel's lab (CIRI, Lyon) in  2010. I deciphered a unknown role of RIG-like helicases in immunosurveillance process (Plos One), and on the control of microbiota and allergy (PNAS). Since 2014, I am group leader in the team of C Caux at the CRCL /Centre Léon Bérard - Lyon, to pursue my investigations on the role of innate sensing during early immunosurveillance processes in the tumoral context.

Scientific summary

In the Caux lab, we are interested in understanding the mechanisms of innate immune surveillance during early stages (oncogenic stress / pre-neoplastic stage) of tumorigenesis. Although diverse innate immune cells likely contribute to tumor sensing, it’s mainly cellular stress detection by NK cell through NKG2D/NKG2DL interaction that is so far established to mediate tumor recognition. In my group, we will focus on Breast Cancer and Colon carcinoma and use unbiased system biology and biologically-driven approaches, both in human and mice, to identify important mechanisms of immune sensing of the very early stages of cell transformation. To achieve this goal, we will have two complementary approaches:

Understand tumor intrinsic mechanisms leading to early immune detection

 Herein we hypothesized that immune surveillance is initiated early during transformation through oncogenic stress. This is supported by the literature and by our data showing that oncogenic stress induced by Sp1 transcription factor accumulation is detected through an innate intrinsic pathway (RIG-like receptors) and results in innate immune cell sensing (Dupuis-Maurin, Plos One 2015).

To decipher the underlying mechanisms in vitro in human and in vivo in mice, we have developed approaches based on mammary epithelial cell lines expressing an inducible oncogene, and co-culture assays with innate immune cells. Based on our preliminary results, we are currently focusing on internal stress innate sensor candidates and deciphering their contribution in early immune detection by neutrophils using pharmacologic inhibitors and genome editing. In complement, in a mouse mammary tumor model where oncogenic stress leads to tumor rejection in immunocompetent (wt) mice but not in immunodeficient mice, an unbiased genome editing in vivo screen will be performed to select tumor clones developing in wt mice and to discover molecular pathways operating in the tumor cell leading to immune detection.

Role of neutrophils and other innate immune cell (Dendritic Cell subsets, NK) crosstalk in early tumor immune surveillance

Thanks to a collaboration with the anti-cancer center Léon Bérard, we have access to human early tumor lesions (Hyperplasia and In Situ Breast Carcinoma, and Colon polyps). We have also acquired a fine knowledge of pre-neoplastic stages in a spontaneous mouse mammary carcinogenesis model. Here we plan to perform a comprehensive analysis of the functional/activation status of neutrophils and other innate immune cells (collaboration J Valladeau-Guilemond and N Bendriss-Vermare groups) in early compared to invasive tumors in human and mice using state-of-the-art technologies: 1) CytOF and deep scRNAseq of tumor-infiltrating neutrophils and other innate immune cells, associated to advanced computational and system biology; 2) multi-immunofluorescence of selected early immune surveillance pathway(s); 3) evaluation of their role in in vitro models (pre-neoplastic organoids and co-culture assays with innate immune cells) and in vivo in mice.