The ability to accurately characterize DNA variant proportions using PCR amplification is key to many genetic studies, including studying tumor heterogeneity, 16S microbiome, viral and immune receptor sequencing. We develop a novel generalizable ultrasensitive amplicon barcoding approach that significantly reduces the inflation/deflation of DNA variant proportions due to PCR amplification biases and sequencing errors. This method was applied to immune receptor sequencing, where it significantly improves the quality and estimation of diversity of the resulting library.
MHC class I (MHC‐I) molecules undergo an intricate folding process in order to pick up antigenic peptide to present to the immune system. In recent years, the discovery of a new peptide editor for MHC‐I has added an extra level of complexity in our understanding of how peptide presentation is regulated. On top of this, the incredible diversity in MHC‐I molecules leads to significant variation in the interaction between MHC‐I and components of the antigen processing and presentation pathway. Here, we review our current understanding regarding how polymorphisms in human leukocyte antigen class I molecules influence their interactions with key components of the antigen processing and presentation pathway. A deeper understanding of this may offer new insights regarding how apparently subtle variation in MHC‐I can have a significant impact on susceptibility to disease.
Low tumour immunogenicity is a major hurdle to overcome in the treatment of cancers with immunotherapies. Here, we reveal a novel therapeutic approach to increase tumour immunogenicity. By delivering the major histocompatibility complex class I (MHC-I) peptide exchange catalyst TAPBPR in an antibody-mediated manner onto the plasma membrane of tumour cells, extracellular MHC-I become highly peptide-receptive. Upon exposure to low doses of exogenous peptide, MHC-I molecules on tumour cells are efficiently loaded with immunogenic antigens, including those derived from human cytomegalovirus and Epstein-Barr virus. TAPBPR-antibody fusion proteins were delivered specifically to tumours in vivo. Finally, antigen-specific CD8+ T cells respond to tumour cells in a targeted manner and can mediate killing of antibody target-positive cells. As memory T cells specific for previously encountered common viruses patrol tumours, TAPBPR-based therapeutics could offer an attractive means to redirected virus-specific T cells against tumours in the fight against cancer.
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