CD28H STIMULATION ENHANCES NK CELL KILLING ACTIVITIES

摘要

CD28H (TMIGD2 or IGPR-1) belongs to the CD28 family and is a transmembrane protein with an immunoglobulin-like extracellular domain, a transmembrane domain and a cytoplasmic tail. The main objective of the inventors was to evaluate the consequences of CD28H stimulation on NK with a monoclonal anti-CD28H antibody (clone 4-5) known to activate T cells. The inventors show that circulating CD56bright and CD56dim NK cells express the same level of CD28H. Circulating CD28H+ NK cells are more activated than CD28Hneg, in fact NK CD28H+ cells express more CD69, NKp30 and Nkp46. The agonist anti-CD28H mAb induces a calcium flux in NK cells while the blocking mAb does not. Calcium flux evaluation shows that CD28H synergize with NKP46 but not with CD16. After an overnight stimulation with the agonist anti-CD28H mAb, NK cells express more CD69, Nkp30, NKG2D and less CD16 compared to a control condition with an isotype mAb. This reflects a very strong activation of NK cells. Moreover, the CD28H-primed NK cells treated with the agonistic anti-CD28H mAb secret more granzyme B and more IFN-g in presence of K562. CD28H-primed NK cells increase their cytotoxic capacities against tumor cell lines. When used in vivo in a xeno-GVHD model in NSG-SGM3 mice, the agonistic anti-CD28H mAb increases the frequency of NK cells suggesting a potential role of CD28H in NK homeostasis. Thus CD28H is a strong activator of NK cells and is the potential new therapeutic target for cancer immunotherapy