Dendritic cell-derived exosomes promote natural killer cell activation and proliferation: a role for NKG2D ligands and IL-15Ralpha.
Dendritic cell (DC) derived-exosomes (Dex) are nanomeric vesicles harboring functional MHC/peptide complexes promoting T cell-dependent tumor rejection. In the first Phase I trial using peptide-pulsed Dex, the observation of clinical regressions in the absence of T cell responses prompted the search for alternate effector mechanisms. Mouse studies unraveled the bioactivity of Dex on NK cells. Indeed, Dex promoted an IL-15Ralpha- and NKG2D-dependent NK cell proliferation and activation respectively, resulting in anti-metastatic effects mediated by NK1.1(+) cells. In humans, Dex express functional IL-15Ralpha which allow proliferation and IFNgamma secretion by NK cells. In contrast to immature DC, human Dex harbor NKG2D ligands on their surface leading to a direct engagement of NKG2D and NK cell activation ex vivo. In our phase I clinical trial, we highlight the capacity of Dex based-vaccines to restore the number and NKG2D-dependent function of NK cells in 7/14 patients. Altogether, these data provide a mechanistic explanation on how Dex may stimulate non MHC restricted-anti-tumor effectors and induce tumor regression in vivo.
Viaud
Sophie
S
Institut National de la Santé et de la Recherche Médicale, Unité 805, Villejuif, France.
Terme
Magali
M
Flament
Caroline
C
Taieb
Julien
J
André
Fabrice
F
Novault
Sophie
S
Escudier
Bernard
B
Robert
Caroline
C
Caillat-Zucman
Sophie
S
Tursz
Thomas
T
Zitvogel
Laurence
L
Chaput
Nathalie
N