Discovery of conserved peptide-MHC epitopes for directly alloreactive CD8 T cells.

Mass Spectrometry allied with generation of activated alloreactive T cell populations and tetramer screening facilitates the identification of endogenous peptides that are directly recognised in complex with allogeneic Major Histocompatibility class I (MHC I) molecules by alloreactive CD8 T cells. We had previously used this approach for the discovery of immunogenic self-peptides presented by the allomorph H-2K (K). In this study, we identified 22 highly immunogenic self-peptides presented by H-2K (K).

A first-in-class pan-lysyl oxidase inhibitor impairs stromal remodeling and enhances gemcitabine response and survival in pancreatic cancer.

The lysyl oxidase family represents a promising target in stromal targeting of solid tumors due to the importance of this family in crosslinking and stabilizing fibrillar collagens and its known role in tumor desmoplasia. Using small-molecule drug-design approaches, we generated and validated PXS-5505, a first-in-class highly selective and potent pan-lysyl oxidase inhibitor. We demonstrate in vitro and in vivo that pan-lysyl oxidase inhibition decreases chemotherapy-induced pancreatic tumor desmoplasia and stiffness, reduces cancer cell invasion and metastasis, improves tumor perfusion and enhances the efficacy of chemotherapy in the autochthonous genetically engineered KPC model, while also demonstrating antifibrotic effects in human patient-derived xenograft models of pancreatic cancer.