Abstract IA09: RiboSeq and ye shall find: Noncanonical protein translation in cancer Iimunosurveillance

Abstract

Abstract By displaying oligopeptides on the cell surface, class I major histocompatibility complex (MHC-I) molecules enable CD8+ T cell immunosurveillance of tumor cells. MHC-I peptide ligands derive proteins synthesized by cancer cells. A number of lines of evidence indicate that many MHC-I peptides derive from a pool of rapidly degraded defective ribosomal products (DRiPs). DRiPs include misfolded gene products resulting from errors in transcription, translation, folding, targeting, and assembly. They also encompass the translation products of “immunoribosomes,” specialized ribosomes proposed to generate antigenic peptides for the express propose of immunosurveillance. There are now several examples in which noncanonical translation efficiently generates peptides for immunosurveillance. I will discuss how the method of ribosome profiling can be used to identify novel tumor target peptides for immunotherapy arising from noncanonical translation. To determine whether ribosome heterogeneity itself can also selectively increase antigenic peptide generation, we screened a lentiviral shRNA library targeting each of the 80 human ribosomal protein genes. We identified candidate genes by alterations in steady state class I molecule expression (a measure of overall peptide supply) or in the ratio of source proteins to source protein-derived peptides. Two ribosomal proteins that either increase or decrease the efficiency of peptide generation are near neighbors on the ribosome surface, suggesting possible mechanisms for influencing peptide generation. Citation Format: Jonathan W. Yewdell. RiboSeq and ye shall find: Noncanonical protein translation in cancer Iimunosurveillance [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr IA09.