Research Papers:
Chemical complementarity of tumor resident, T-cell receptor CDR3s and renalase-1 correlates with increased melanoma survival
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Abstract
Saif Zaman1, Fred S. Gorelick2,3, Andrea Chrobrutskiy4, Boris I. Chobrutskiy5, Gary V. Desir1,2 and George Blanck6,7
1 Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06510, USA
2 Veteran’s Administration Healthcare System, CT 06516, USA
3 Department of Cell Biology, Yale School of Medicine, New Haven, CT 06511, USA
4 Department of Pediatrics, Oregon Health and Science University Hospital, Portland, OR 97239, USA
5 Department of Internal Medicine, Oregon Health and Science University Hospital, Portland, OR 97239, USA
6 Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, FL 33612, USA
7 Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
Correspondence to:
George Blanck, | email: | [email protected] |
Keywords: RNLS; melanoma; T-cell receptor CDR3s; chemical complementarity
Received: June 17, 2024 Accepted: July 02, 2024 Published: August 05, 2024
ABSTRACT
Overexpression of the secretory protein renalase-1 negatively impacts the survival of melanoma and pancreatic cancer patients, while inhibition of renalase-1 signaling drives tumor rejection by promoting T-cell activation. Thus, we investigated the chemical complementarity between melanoma-resident, T-cell receptor (TCR) complementarity-determining region 3 (CDR3) amino acid sequences (AAs) and the renalase-1 protein. Increasing complementarity of TCR CDR3s to renalase-1 AAs, as assessed by a chemical complementarity scoring algorithm, was associated with improved overall survival (OS) in melanoma patients. The expression levels of several immune signature genes were significantly, positively correlated with increasing TCR CDR3-renalase-1 complementarity scores. Additionally, the survival association observed with high complementarity of TCR CDR3s to renalase-1 AAs was more robust in cases with low renalase-1 gene expression levels. Mapping of TCR CDR3-renalase-1 in silico interaction sites identified major epitope candidates including RP220, the signaling module of the renalase-1 protein, consistent with the fact that a monoclonal antibody to RP220 is a potent inhibitor of melanoma growth. These findings indicate that renalase-1 is a potential antigen for TCR recognition in melanoma and could be considered as a target for immunotherapy.
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