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Published on: May 24, 2019
DDX10 Exacerbates Exosomal PD-L1-Dependent T Cell Exhaustion via Phase Separation of Rab27b in Oral Squamous Cell
1Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, Guangdong 510280, China.
Abstract:
DEAD-box ATPase 10 (DDX10), a prominent RNA-binding protein in the DDX family, has a critical function in cancer progression. Nevertheless, its well-defined mechanisms in oral squamous cell carcinoma (OSCC) are still not well understood. Here, we identify that DDX10 is substantially increased in OSCC, which is positively correlated with poor prognosis and malignant behavior. Mechanistically, we found that DDX10 had physical interaction with Rab27b by undergoing phase separation. Knockdown of DDX10 inhibited Rab27b-mediated exosome secretion and the expression of programmed cell death-ligand 1 (PD-L1) within its contents. Furthermore, knocking down DDX10 could restore the function and infiltration of T cells, hence inhibiting the progression of OSCC. These findings highlight that the oncogenic role of DDX10 in promoting exosomal PD-L1 secretion via phase separation with Rab27b has been preliminarily validated in T cell exhaustion in OSCC. A potential strategy for improving OSCC immunotherapy may involve the inhibition of DDX10.
Insights
DEAD-box ATPase 10 (DDX10) is elevated in oral squamous cell carcinoma (OSCC), driving cancer progression. Inhibiting DDX10 reduces exosomal PD-L1 and restores T cell function, offering a potential immunotherapy strategy for OSCC.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- DEAD-box ATPase 10 (DDX10) is an RNA-binding protein implicated in cancer progression.
- The specific role and mechanisms of DDX10 in oral squamous cell carcinoma (OSCC) remain unclear.
Purpose of the Study:
- To investigate the function and mechanism of DDX10 in oral squamous cell carcinoma (OSCC).
- To explore DDX10's role in regulating exosome secretion and T cell exhaustion in OSCC.
Main Methods:
- Quantitative analysis of DDX10 expression in OSCC tissues.
- Investigation of DDX10's interaction with Rab27b using phase separation.
- Assessment of exosome secretion and PD-L1 expression upon DDX10 knockdown.
- Evaluation of T cell function and infiltration in response to DDX10 modulation.
Main Results:
- DDX10 expression is significantly increased in OSCC and correlates with poor prognosis.
- DDX10 interacts with Rab27b via phase separation, inhibiting Rab27b-mediated exosome secretion.
- Knockdown of DDX10 reduces exosomal programmed cell death-ligand 1 (PD-L1) and restores T cell activity.
- DDX10 promotes OSCC progression by inducing T cell exhaustion through exosomal PD-L1.
Conclusions:
- DDX10 acts as an oncogene in OSCC by promoting exosomal PD-L1 secretion via phase separation with Rab27b.
- DDX10 contributes to T cell exhaustion in the OSCC tumor microenvironment.
- Inhibition of DDX10 presents a potential therapeutic strategy for enhancing OSCC immunotherapy.
