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Boosting Natural Killer Cell-Based Cancer Immunotherapy with Selenocystine/Transforming Growth Factor-Beta
Chang Liu1, Haoqiang Lai1, Tianfeng Chen1
1The First Affiliated Hospital and Department of Chemistry, Jinan University, Guangzhou 510632, China.
Abstract:
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.
Insights
This study developed a nanoemulsion system to co-deliver drugs, enhancing natural killer (NK) cell immunotherapy. The system effectively boosts NK cell cancer-killing ability, particularly against triple-negative breast cancer (TNBC).
Area of Science:
- Immunotherapy
- Nanomedicine
- Cancer Biology
Background:
- Natural killer (NK) cell immunotherapy shows promise for cancer treatment but faces challenges like reduced tumor cell ligands and immunosuppressive tumor microenvironments, such as transforming growth factor-beta (TGF-β).
- Overcoming these limitations is crucial for effective NK cell-mediated cancer lysis.
Purpose of the Study:
- To develop a nanoemulsion system (SSB NMs) for co-delivery of a TGF-β inhibitor and selenocysteine (SeC) to enhance NK cell immunotherapy efficacy.
- To investigate the mechanisms underlying the enhanced anti-cancer effects of SSB NMs in triple-negative breast cancer (TNBC).
Main Methods:
- Development of a nanoemulsion system (SSB NMs) for co-delivering TGF-β inhibitor and SeC.
- Assessment of SSB NMs' effect on NK92 cell lytic potency and sensitization of MDA-MB-231 TNBC cells to patient-derived NK cells.
- Mechanistic studies involving NKG2D/NKG2DL signaling, DNA damage response, and TGF-β/Smad2/3 pathway inhibition.
- In vivo evaluation of SSB NMs' therapeutic effects in combination with NK92 cells.
Main Results:
- SSB NMs significantly enhanced NK92 cell lytic potency by 2.1-fold.
- SSB NMs sensitized TNBC cells to NK cells, increasing cancer lysis by up to 13.8-fold.
- Mechanisms involved enhanced NKG2D/NKG2DL signaling, DNA damage response, and suppressed TGF-β signaling, leading to increased NKG2DL and NKG2D expression.
- SSB NMs demonstrated significant in vivo anticancer effects through sustained drug release and synergy with NK92 cells.
Conclusions:
- The developed nanoemulsion system (SSB NMs) effectively co-delivers synergistic drugs to enhance NK cell immunotherapy.
- SSB NMs show significant potential for treating breast cancer, especially TNBC, by overcoming tumor microenvironment suppression and enhancing NK cell recognition and killing.
- This study provides insights into nanoemulsion design for drug co-delivery and the mechanisms of NK cell adaptive therapy.
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