HLA-Shuttle: A system for enhancing antigen presentation in immunologically cold tumors
- Daniel Hwang
- Molly C. Erdman
- Santosh Adhikari
- Ram Pantula
- Kaya Epstein
- Peiyao Li
- Francesca Costabile
- Photis Rotsides
- Chloe S. Wang
- Shirley M. Sun
- Hossein Fazelinia
- Lynn A. Spruce
- Tim Fugmann
- Trendelina Rrustemi
- Wai Tuck Soh
- Alvin Farrel
- Muzamil Y. Want
- Andrea Facciabene
- Mustafa Mir
- John M. Maris
- Nikolaos G. Sgourakis
2026-01-01
Epitopic peptides presented by class-I human leukocyte antigen (HLA-I) proteins provide the basis of immune surveillance by T cells. Conversely, reduced surface HLA-I expression is a hallmark of immune evasion by latent viral infections and cancer, which confounds the identification of peptide antigens and neoantigens. Here, we outline a system (HLA-Shuttle) for in vitro manipulation of cells with engineered components of the HLA-I processing machinery to confer a continuum of chaperoning activity throughout their trafficking pathway. HLA-Shuttle restores antigen presentation in immunologically cold neuroblastoma cells, enabling identification of multiple tumor-associated antigens with therapeutic potential. Cellular trafficking assays and single-particle tracking reveal a global stabilization of HLA-I molecules, extension of their cell-surface lifetime and microdomain formation. HLA-Shuttle can be used across a range of aberrant cellular states where low antigen expression remains a bottleneck for the identification of endogenous peptide antigens.