UCLA researchers from the Department of Pediatrics-Allergy/Immunology have developed a novel platform to reverse engineer vaccine antigens for the prevention and treatment of infectious disease and cancer.
BACKGROUND: Vaccines function by introducing antigens into a host to stimulate an immune response, providing protection against pathogens and certain cancers. The process of developing a novel vaccine is usually lengthy due to challenges in to determining which antigens from the pathogen in question are capable of eliciting effective immunity in a broad swath of human recipients. Researchers at UCLA have addressed this challenge by developing new methods for screening libraries of peptide ligands that can productively interact with T cell receptors (TCRs) on T cells to elicit an immune response. Similar methods are based on the binding affinity between the pMHC and TCR; however, strong binding does not always result in TCR activation, which is necessary for triggering a protective response. Therefore, there is a need for improved techniques to identify vaccine antigens that reliable activate TCRs to provide immunity.
INNOVATION: Researchers at UCLA have designed a novel approach to vaccine design that leverages the interaction between T cells and their counterpart APCs. Researchers engineered APCs to express a fluorescently tagged protein that provides a readout for peptide-activated T cell interactions, enabling the identification of productive TCR-APC interactions. By co-culturing synthetic APCs in vitro with T cells bearing the key TCRs, they demonstrated that (i) T cells are activated by the artificial APCs presenting an effective antigen, (ii) APCs receive back a signal from the cognate-activated T cell, (iii) T cell feedback driving APC fluorescence is specific to productive pMHC-TCR interactions, and (iv) the system can sensitively identify useful peptides. Researchers also modified APCs to present altered peptide ligands with lower T cell specificity in vitro, resulting in reduced fluorescence compared to high-specificity T cells, demonstrating the tunability of the system. To discover novel antigens using the described platform, researchers computationally generated a library of 18,000 peptides and introduced this library construct into the synthetic APCs. Productive interactions were identified via fluorescence and bulk sequencing of the APCs, revealing peptides capable of activating T cells and validating the platform’s ability to identify novel synthetic antigens. To discover novel TCRs in a disease model, UCLA researchers conducted single-cell sequencing on tumor-infiltrating lymphocytes (TILs) from mice injected with cancer and found cancer-relevant TCRs. Culturing of the TILs with synthetic APCs expressing the 18,000 peptide library revealed peptides that were then later successfully tested in a cancer prophylaxis model, demonstrating the utility of novel peptides to protect from cancer. In summary, UCLA researchers have developed a new platform to discover peptide antigens as vaccines.
POTENTIAL APPLICATIONS:
- Vaccine development for prevention of infectious disease
- Vaccine manufacturing for cancer prevention and immunotherapy
ADVANTAGES:
- The unbiased antigen discovery platform is synthetic and is not limited to a restricted library of peptides from the pathogen’s proteome or cancer-mutated proteins
- Using a low-complexity peptide library can reduce costs throughout the antigen discovery process
DEVELOPMENT-TO-DATE: UCLA researchers have developed an in vitro platform to identify novel, synthetic peptides and have applied the platform to identify novel antigens in the context of an in vivo mouse cancer model.
KEYWORDS: Vaccine, antigen, neoantigen, immune response, pMHC, TCR, APC, T cell activation, peptide library, bulk sequencing, single-cell sequencing, TILs