Chaperone Molecules Found to Enhance Immune Response

Researchers at Children’s Hospital of Philadelphia (CHOP) have made a significant discovery that could enhance cell therapy and immunization, according to an article published in Science Advances. The researchers identified variants of a chaperone molecule that assists with foreign antigens circulating the immune system.

The Class I major histocompatibility complex (MHC-I) proteins help create peptides on the cell surface, providing the cell with means of identifying antigens. The process requires several molecules, including molecular chaperones that assist with MHC-I folding. TAPBPR is a molecular chaperone that facilitates peptide loading and is particularly suitable for clinical applications requiring peptide exchange. However, its use is limited as some HLA allotypes do not interact with the molecule, making the development of novel therapies challenging.

To overcome this challenge, the CHOP researchers analyzed three different TAPBPR proteins and found that chicken TAPBPR reacted with multiple HLA allotypes, including many that could not bind to human TAPBPR. They also demonstrated that TAPBPR stabilizes the empty MHC-I groove in an “open” conformation, boosting its affinity for peptide loading. The team, along with collaborators at the University of Illinois, found a variant of the human TAPBPR that mimics the chicken sequence, enhancing peptide exchange across a broad range of HLA types.

“Although the highly polymorphic nature of MHC-I molecules makes it challenging to engineer ‘universal’ chaperones, our research team demonstrated that both a chicken ortholog of TAPBPR and a human variant with minor adjustments could enhance peptide exchange across multiple disease-relevant HLAs,” explains senior author Nikolaos G. Sgourakis, Ph.D., Associate Professor in the Center for Computational and Genomic Medicine at Children’s Hospital of Philadelphia.

“These TAPBPR orthologs could be utilized in various cancer immunotherapeutic settings to narrow the peptide repertoire and increase immunogenicity,” Sgourakis continues. “The knowledge gained by our studies can guide the design of engineered TAPBPR variants with tailored HLA specificity and catalytic efficiency for peptide exchange applications both in vitro and in vivo.”

With this discovery, researchers may be able to engineer universal chaperones that enhance peptide exchange across a broad range of HLA types. The enhanced efficiency of peptide exchange can increase the immunogenicity of cancer cells, providing a new way to fight cancer. The knowledge gained from this study could also pave the way for designing new vaccines and immunotherapeutic agents, improving the body’s ability to fight against infectious diseases.