Characterization of the role of the extracellular matrix component PRELP on the immunogenicity of tumors

• Applicant: Dr. Karthikeyan Subbarayan
• Subject Area: Clinical Immunology and Allergology ; Hematology, Oncology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 558635546

Although immunotherapies have revolutionized the treatment of advanced cutaneous melanoma, only a limited number of melanoma patients have a durable response. A better understanding of the interaction of melanoma cells with the microenvironment, including extracellular matrix (ECM) components, might provide novel therapeutic options. Although the ECM has been linked to several hallmarks of cancer, little information is available regarding the expression and function of the ECM protein purine-arginine-rich and leucine-rich protein (PRELP) in cancer, including melanoma. The proposed research is based on the central hypothesis that the reduced PRELP expression in tumors is associated with a tumorigenic phenotype and evasion of immune surveillance. Own preliminary studies showed a reduced PRELP expression in skin cutaneous melanoma when compared to adjacent normal tissues, which was associated with reduced patients’ survival. PRELP expression was higher in responders to immune checkpoint inhibitor therapy compared to non-responders, and higher PRELP expression correlated with improved survival in metastatic melanoma patients treated with checkpoint blockade. Transfection of PRELP into melanoma cell lines restored MHC class I surface expression due to transcriptional upregulation of components of the MHC class I antigen processing machinery and IFN-gamma signal transduction pathway, impaired TGF-ß signaling, reduced cell proliferation, migration and invasion of melanoma cells as well as the secretion of high CCL5 concentrations in the cell supernatant. Based on these preliminary studies, the overall objective of this proposal is to investigate the expression and function of PRELP and its correlation with the expression of immune modulatory molecules, immune cell infiltration and clinical parameters using melanoma cell lines and melanoma lesions as well as in silico analyses of public available databases. In addition, PRELP interacting microRNAs and membrane proteins and PRELP-regulated gene/proteins in particular involved in signal transduction and oncogenic pathways will be identified. These data will give insights into the role of PRELP (i) as a potential regulator of tumorgenicity and immunogenicity of the melanoma microenvironment, (ii) as a prognostic marker for predicting disease progression and/or therapy response and (iii) in the reversion of the tumorigenic phenotype thereby representing a novel therapeutic option for melanoma.

• DFG Programme: Research Grants
• International Connection: Switzerland
• Cooperation Partner: Professor Dr. Mitch Levesque