Conclusions
Targeting OASL enhances the immune response in PDAC, providing a novel therapeutic strategy to improve outcomes in PDAC patients.
Methods
Bioinformatic analyses were used to identify key factors associated with low-CTLs infiltration in PDAC and the role of oligoadenylate synthetase-like (OASL) was mainly focused in our study. Immunohistochemistry (IHC) was used to assess the relationship between the expression of OASL and the prognosis of patients. Western blotting, Flow cytometry, Co-immunoprecipitation and Immunofluorescence were applied to elucidate the molecular mechanism by which OASL mediates immune escape in PDAC. The orthotopic PDAC models were constructed to evaluate the effects of OASL-knockdown on CD8+ T cells infiltration and tumor growth in vivo.
Results
OASL was found to be significantly upregulated in PDAC and negatively correlated with the major histocompatibility complex class I (MHC-I) expression, which is associated with worse patient prognosis. Notably, OASL-knockdown leads to a significant increase in CD8+ T cell infiltration and slows tumor growth in vivo. Mechanistic studies revealed that OASL -knockdown restored the total and surface MHC-I level through impairing neighbor of BRCA1 gene 1 (NBR1)-mediated autophagy-lysosomal degradation of MHC-I. Conclusions: Targeting OASL enhances the immune response in PDAC, providing a novel therapeutic strategy to improve outcomes in PDAC patients.