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B4: Control of classical HLA class I antigen by microRNAs and RNA-binding proteins, their impact on immune response and clinical relevance

Supervisor: Prof. Dr. Barbara Seliger 

 

Specific aim(s)/topic(s)

(1) Identification of HLA class I targeting miRs, their functional characterization and clinical significance

(2) Identification and characterization of the function of RNA-binding proteins controlling components of the antigen processing and presentation machinery

 

Background and significance

Hematologic and solid tumors have developed strategies to escape immune surveillance, including abnormalities in the classical HLA antigens, which are directly associated with metastatic properties, disease progression and poor patients survival. The underlying molecular mechanisms of altered HLA class I surface antigen expression are only rarely associated with structural alterations in components of the HLA class I antigen processing and presentation machinery (APM), but are often due to their deregulated expression, which can occur at the epigenetic, transcriptional and post-transcriptional level . Altered gene expression in tumors can be controlled by diverse mechanisms including post-transcriptional mechanisms involving RNA-binding proteins (RBP) as well as microRNAs (miRs). Indeed, miRs have been identified that regulate the expression of immunomodulatory molecules, thereby also affecting the immune responses. While the post-transcriptional regulation of HLA class I APM components has not yet been defined in detail, their regulation appears to be a key process in tumor development by altering the immunogenicity of tumors. The expression and function of different HLA class I APM components, in particular of the peptide transporters TAP1 and TAP2 as well as of tapasin, has been found to be impaired in many tumors, but miRs and RBPs targeting these molecules have not yet been identified in these malignancies. Thus, miRs and RBPs that control TAP and/or tapasin in tumor cells will be identified.