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TGF-β regulated leukemia cell susceptibility against NK targeting through the down-regulation of the CD48 expression
Chin-Han Huang1, Yi-Jen Liao2, Tzeon-Jye Chiou3
1Department of Biotechnology and Laboratory Science in Medicine, School of Biomedical Science and Engineering, National Yang-Ming University, Taipei, Taiwan.
Abstract:
Transforming growth factor-β (TGF-β) is known to function as a dual role regulatory cytokine for being either a suppresser or promoter during tumor initiation and progression. In solid tumors, TGF-β secreted from tumor microenvironment acts as a suppresser against host immunity, like natural killer (NK) cells, to favor tumor evasion. However, besides solid tumors, the underlying mechanism of how TGF-β regulates leukemogenesis, tumor progression, immunoediting, and NK function is still not clear in detail. In this study, we found that TGF-β induced leukemia MEG-01 and U937 cells to become less sensitive to NK-92MI targeting by down-regulating CD48, a ligand for NK activating receptor 2B4, but not down-regulating other tumor-associated carbohydrate antigens (TACAs). In CD48-knockdown cells, cells responding to NK-92MI targeting displayed a phenotype of less NK susceptibility and cell conjugation. On the other hand, when NK cells were treated with TGF-β, TGF-β suppressed NK recognition, degranulation, and killing activity in time-dependent manner by regulating ICAM-1 binding capacity instead of affecting expressions of activating and inhibitory receptors. Taken together, both leukemia cells and immune NK cells could be regulated by TGF-β through suppressing leukemia cell surface CD48 to escape from host surveillance and down-regulating NK cell surface ICAM-1 binding activity to impair NK functions, respectively. Our results suggested that TGF-β had effect in leukemia similar to that observed in solid tumors but through different regulatory mechanism.
Insights
Transforming growth factor-β (TGF-β) suppresses leukemia cell recognition by natural killer (NK) cells via CD48 downregulation. TGF-β also impairs NK cell function, aiding leukemia immune evasion.
Area of Science:
- Immunology
- Cancer Biology
- Hematology
Background:
- Transforming growth factor-β (TGF-β) has a dual role in cancer, acting as a suppressor or promoter.
- In solid tumors, TGF-β inhibits natural killer (NK) cell immunity, facilitating tumor evasion.
- The precise mechanisms by which TGF-β influences leukemogenesis and NK cell function remain unclear.
Purpose of the Study:
- To investigate the role of TGF-β in regulating leukemia cell sensitivity to NK cell targeting.
- To elucidate how TGF-β affects NK cell activity and recognition of leukemia cells.
- To understand the molecular mechanisms underlying TGF-β's influence on the leukemia-NK cell interaction.
Main Methods:
- Leukemia cell lines (MEG-01, U937) and NK cell line (NK-92MI) were utilized.
- Flow cytometry and cell conjugation assays were performed to assess NK cell targeting and leukemia cell susceptibility.
- Quantitative analysis of cell surface markers (CD48, TACAs, ICAM-1) and NK cell functions (degranulation, killing activity) was conducted.
Main Results:
- TGF-β treatment reduced leukemia cell sensitivity to NK-92MI cells by downregulating CD48, a ligand for the NK receptor 2B4.
- CD48 knockdown in leukemia cells resulted in decreased NK cell susceptibility and impaired cell conjugation.
- TGF-β suppressed NK cell recognition, degranulation, and killing activity in a time-dependent manner, primarily by affecting ICAM-1 binding capacity.
Conclusions:
- TGF-β promotes leukemia immune evasion by downregulating CD48 on leukemia cells, reducing their susceptibility to NK cell surveillance.
- TGF-β impairs NK cell function by reducing ICAM-1 binding capacity, thereby hindering NK cell-mediated cytotoxicity.
- These findings reveal distinct mechanisms of TGF-β action in leukemia compared to solid tumors, highlighting its multifaceted role in cancer immunity.
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