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Targeting Innate Lymphoid Cells

Periodic Reporting for period 2 - TILC (Targeting Innate Lymphoid Cells)

Reporting period: 2018-07-01 to 2019-12-31

"TILC focuses on Innate Lymphoid Cells (ILCs). ILCs are a newly discovered type of lymphocyte, and their study opens up new perspectives for understanding and manipulating of immunity. ILCs include cytotoxic ILCs (NK cells) and helper-like ILCs (ILC1, ILC2 & ILC3). Studies of ILC2 cells have advanced considerably, but much remains unknown about the respective roles of NK, ILC1 and ILC3 cells. TILC aims to explore new frontiers in ILC biology, by focusing on these subsets of ILCs in mice and humans, through five specific aims.
We originally proposed to address five main issues, as follows:
- Specific aim #1: Generation of novel ILC mouse models
- Specific aim #2: Identification of the ligands of NKp46
- Specific aim #3: What role do NKp46+ILCs play in cancer immunosurveillance?
- Specific aim #4: How do NKp46+ILCs participate in gut homeostasis?
- Specific aim #5: What are the consequences of NKp46+ILC-deficiencies in humans?

The specific aims of TILC are being conducted as scheduled and led to several publications in highly visible journals since the start of the program. The trhree most important publications are:
1. Crinier A., Milpied P., Escalière B., Piperoglou C., Galluso J., Balsamo A., Spinelli L., Cervera-Marzal I., Ebbo M., Girard-Madoux M., Jaeger J., Bollon E., Hamed S., Hardwigsen J., Ugolini S., Narni-Mancinelli E., Vivier E. Definition of Natural Killer cell heterogeneity in human and mouse by high-throughput single-cell RNA sequencing. Immunity, 2018, 49: 971–986.
2. André P., Denis C., Soulas C., Bourbon-Caillet C., Lopez J., Arnoux T., Bléry M., Bonnafous C., Gauthier L., Morel A., Rossi B., Remark R., Breso V., Bonnet E., Habif G., Guia S., Lalanne A.I. Hoffmann C., Lantz O., Fayette J., Boyer-Chamard A., Zerbib R., Dodion P., Ghadially H., Jure-Kunkel M., Herbst R., Narni-Mancinelli E., Cohen R.B. Vivier E. Anti-NKG2A mAb is a checkpoint inhibitor that promotes anti-tumor immunity by unleashing both T and NK cells. Cell, 2018, 175.
3. Gauthier L., Morel A., Anceriz N., Rossi B., Blanchard-Alvarez A., Grondin G., Trichard S., Cesari C., Sapet M., Bosco F., Rispaud-Blanc H., Guillot F., Cornen S., Roussel A., Amigues B., Habif G., Caraguel F., Arrufat S., Remark R., Romagné R., Morel Y., Narni-Mancinelli E., Vivier E. Multifunctional natural killer cell engagers targeting NKp46 trigger protective tumor immunity. Cell, 2019, 177, 1701–1713.
We are using scRNAseq and have developed ad-hoc bio-informatic expertise to analyze these transcriptomics data. Besides the definition of NK cell heterogeneity in human and mouse by scRNAseq (Crinier et al., Immunity 2018), using the same high-throughput methods, we are now studying human and mouse bone marrow NK cells in normal and acute myeloid leukemia conditions, as well as ILC heterogeneity in normal and colorectal cancer conditions.
We believe that TILC will provide answers to some of the most pressing questions concerning the role and clinical potential of NKp46+ ILCs