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Published on: December 13, 2018
Long-chain polyunsaturated omega-3 fatty acids reduce multiple myeloma exosome-mediated suppression of NK cell
Milad Moloudizargari1, Frank Redegeld2, Mohammad Hossein Asghari3
1Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Background:
Despite the advances in the treatment of multiple myeloma (MM), complete remission is usually challenging. The interactions between tumor and host cells, in which exosomes (EXs) play critical roles, have been shown to be among the major deteriorative tumor-promoting factors herein. Therefore, any endeavor to beneficially target these EX-mediated interactions could be of high importance.
Objectives:
a) To investigate the effects of myeloma EXs on natural killer (NK) cell functions. b) To check whether treatment of myeloma cells with eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA), two polyunsaturated omega-3 fatty acids with known anti-cancer effects, can modify myeloma EXs in terms of their effects on natural killer functions.
Methods:
L363 cells were treated with either EPA or DHA or left untreated and the released EXs (designated as E-EX, D-EX and C-EX, respectively) were used to treat NK cells for functional studies.
Results:
Myeloma EXs (C-EXs) significantly reduced NK cytotoxicity against K562 cells (P ≤ 0.05), while the cytotoxicity suppression was significantly lower (P ≤ 0.05) in the (E-EX)- and (D-EX)-treated NK cells compared to the (C-EX)-treated cells. The expression of the activating NK receptor NKG2D and NK degranulation, after treatment with the EXs, were both altered following the same pattern. However, C-EXs could increase IFN-γ production in NK cells (P < 0.01), which was not significantly affected by EPA/DHA treatment. This indicates a dual effect of myeloma EXs on NK cells functions.
Conclusion:
Our observations showed that myeloma EXs have both suppressive and stimulatory effects on different NK functions. Treatment of myeloma cells with EPA/DHA can reduce the suppressive effects of myeloma EXs while maintaining their stimulatory effects. These findings, together with the previous findings on the anti-cancer effects of EPA/DHA, provide stronger evidence for the repositioning of the currently existing EPA/DHA supplements to be used in the treatment of MM as an adjuvant treatment. EXs released from L363 (myeloma) cells in their steady state increase IFN-γ production of NK cells, while reduce their cytotoxicity against the K562 cell line (right blue trace). EXs from L363 cells pre-treated with either EPA or DHA are weaker stimulators of IFN-γ production. These EXs also increase NK cytotoxicity and NKG2D expression (left brown trace) compared to the EXs obtained from untreated L363 cells. Based on these findings, myeloma EXs have both suppressive and stimulatory effects on different NK functions depending on the properties of their cells of origin, which can be exploited in the treatment of myeloma.
Insights
Omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) can modify multiple myeloma (MM) exosomes to reduce their suppressive effects on natural killer (NK) cells. This suggests EPA and DHA could be repositioned as adjuvant therapies for MM.
Area of Science:
- Immunology
- Cancer Biology
- Biochemistry
Background:
- Multiple myeloma (MM) treatment remains challenging, with tumor-host interactions involving exosomes (EXs) promoting disease progression.
- Targeting exosome-mediated interactions is crucial for developing novel MM therapies.
Purpose of the Study:
- To investigate the impact of MM-derived exosomes (EXs) on natural killer (NK) cell functions.
- To determine if eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA) treatment alters MM EXs' effects on NK cells.
Main Methods:
- MM cells (L363) were treated with EPA, DHA, or left untreated.
- Released exosomes (E-EX, D-EX, C-EX) were isolated and used to treat NK cells for functional assays.
Main Results:
- MM EXs (C-EXs) suppressed NK cell cytotoxicity and NKG2D expression.
- EPA/DHA-treated MM EXs (E-EXs, D-EXs) showed significantly reduced suppression of NK cytotoxicity and NKG2D expression compared to C-EXs.
- MM EXs increased NK cell IFN-γ production, an effect not significantly altered by EPA/DHA treatment, indicating dual effects on NK cell functions.
Conclusions:
- MM EXs exhibit both suppressive and stimulatory effects on distinct NK cell functions.
- EPA/DHA treatment of MM cells modulates their EXs, mitigating suppressive effects on NK cells while preserving stimulatory functions.
- Findings support the repositioning of EPA and DHA as potential adjuvant therapies for MM, leveraging their anti-cancer properties and ability to enhance NK cell-mediated anti-tumor activity.
