Translation dysregulation in cancer as a source for targetable antigens

ABSTRACT: Aberrant peptides presented by major histocompatibility complex (MHC) molecules are targets for tumor eradication, as these peptides can be recognized as foreign by T cells. Protein synthesis in malignant cells is dysregulated, resulting in the production of non-canonical aberrant peptides. We hypothesized that inducing translation aberrations in cancers might reveal neopeptides that can be exploited for T cell-based therapies. To explore this hypothesis, we disrupted translation fidelity by silencing TYW2, a tRNA-yW synthesizing Protein 2 that supports reading-frame maintenance. Using ribosome profiling coupled with immunopeptidomics, we uncover a large set of out-of-frame peptides in TYW2 KO cells and demonstrate that these aberrant peptides are highly immunogenic. Furthermore, we show that Tyw2 loss leads to increased immunogenicity of melanoma tumors in vivo, mediated through cytotoxic T cell activity. Importantly, treatment of Tyw2 KO tumor-bearing mice with anti-PD1 checkpoint blockade therapy further reduces tumor growth, and its reduced expression is associated with increased response to checkpoint blockade therapy in patients. Together, our data shows that defects in translation fidelity indeed contribute to tumor immunogenicity and suggests that they can be harnessed for cancer immunotherapy modalities.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human) Mus Musculus (mouse)

TISSUE(S): Dendritic Cell, Epithelial Cell, Skin, Bone Marrow

DISEASE(S): Acute Leukemia

SUBMITTER: Chen Weller  

LAB HEAD: Yardena Samuels

PROVIDER: PXD053256 | Pride | 2025-03-25

REPOSITORIES: Pride