15 research outputs found
MiR-155 augments CD8+ T-cell antitumor activity in lymphoreplete hosts by enhancing responsiveness to homeostatic γc cytokines
Lymphodepleting regimens are used before adoptive immunotherapy
to augment the antitumor efficacy of transferred T cells by
removing endogenous homeostatic “cytokine sinks.” These conditioning
modalities, however, are often associated with severe toxicities.
We found that microRNA-155 (miR-155) enabled tumorspecific
CD8+ T cells to mediate profound antitumor responses in
lymphoreplete hosts that were not potentiated by immune-ablation.
miR-155 enhanced T-cell responsiveness to limited amounts
of homeostatic γc cytokines, resulting in delayed cellular contraction
and sustained cytokine production. miR-155 restrained the expression
of the inositol 5-phosphatase Ship1, an inhibitor of the serinethreonine
protein kinase Akt, and multiple negative regulators of
signal transducer and activator of transcription 5 (Stat5), including
suppressor of cytokine signaling 1 (Socs1) and the protein tyrosine
phosphatase Ptpn2. Expression of constitutively active Stat5a recapitulated
the survival advantages conferred by miR-155, whereas
constitutive Akt activation promoted sustained effector functions.
Our results indicate that overexpression of miR-155 in tumorspecific
T cells can be used to increase the effectiveness of adoptive
immunotherapies in a cell-intrinsic manner without the need
for life-threatening, lymphodepleting maneuvers.126261sciescopu