posted on 2020-08-12, 16:37authored byChang Liu, Haoqiang Lai, Tianfeng Chen
Natural
killer (NK) cell-based immunotherapy represents a promising
strategy to overcome the bottlenecks of cancer treatment. However,
the therapeutic efficacy is greatly limited by downregulation of recognition
ligands on the tumor cell surface, and the immunosuppressive effects
can be thwarted by the tumor microenvironment such as secretion of
transforming growth factor-beta (TGF-β), which could stunt the
NK cell-mediated immune response. To overcome these limitations, herein
we developed a nanoemulsion system (SSB NMs) to co-deliver TGF-β
inhibitor and selenocysteine (SeC) to achieve amplified anticancer
efficacy. SSB NMs significantly enhanced the lytic potency of NK92
cells by 2.1-fold. Moreover, a subtoxic dose of SSB NMs effectively
sensitized MDA-MB-231 triple-negative breast cancer (TNBC) cells to
NK cells derived from seven clinical patients, resulting in an up
to 13.8-fold increase in cancer lysis. Mechanistic studies reveal
that the sensitizing effects relied on natural killer group 2, member
D (NKG2D)/NKG2D ligands (NKG2DLs) signaling with the involvement of
DNA damage response. SSB NMs also effectively restrained TGF-β/TGF-β
RI/Smad2/3 signaling, which thus enhanced NKG2DL expression on tumor
cells and stimulated NKG2D surface expression on NK92 cells, ultimately
contributing to the enhanced immune response. Furthermore, SSB NMs
sustained release of SeC and TGF-β inhibitor and synergized
with NK92 cells to induce significant anticancer effects in
vivo. Together, this study not only demonstrates a simple
strategy for the design of a nanoemulsion to co-deliver synergistic
drugs but also sheds light on the application and action mechanisms
in NK cell adaptive therapy against breast cancer, especially TNBCs.