Pharmacologic modulation of RNA splicing enhances anti-tumor immunity

Cell. 2021 Jul 22;184(15):4032-4047.e31. doi: 10.1016/j.cell.2021.05.038. Epub 2021 Jun 24.


Although mutations in DNA are the best-studied source of neoantigens that determine response to immune checkpoint blockade, alterations in RNA splicing within cancer cells could similarly result in neoepitope production. However, the endogenous antigenicity and clinical potential of such splicing-derived epitopes have not been tested. Here, we demonstrate that pharmacologic modulation of splicing via specific drug classes generates bona fide neoantigens and elicits anti-tumor immunity, augmenting checkpoint immunotherapy. Splicing modulation inhibited tumor growth and enhanced checkpoint blockade in a manner dependent on host T cells and peptides presented on tumor MHC class I. Splicing modulation induced stereotyped splicing changes across tumor types, altering the MHC I-bound immunopeptidome to yield splicing-derived neoepitopes that trigger an anti-tumor T cell response in vivo. These data definitively identify splicing modulation as an untapped source of immunogenic peptides and provide a means to enhance response to checkpoint blockade that is readily translatable to the clinic.

Keywords: PD1; PRMTs; RBM39; RNA splicing; immune checkpoint blockade; immunopeptidome; immunotherapy; neoantigens; neoepitopes; splicing.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigen Presentation / drug effects
  • Antigen Presentation / immunology
  • Antigens, Neoplasm / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Epitopes / immunology
  • Ethylenediamines / pharmacology
  • Gene Expression Regulation, Neoplastic / drug effects
  • Hematopoiesis / drug effects
  • Hematopoiesis / genetics
  • Histocompatibility Antigens Class I / metabolism
  • Humans
  • Immune Checkpoint Inhibitors / pharmacology
  • Immunotherapy
  • Inflammation / pathology
  • Mice, Inbred C57BL
  • Neoplasms / genetics*
  • Neoplasms / immunology*
  • Peptides / metabolism
  • Protein Isoforms / metabolism
  • Pyrroles / pharmacology
  • RNA Splicing / drug effects
  • RNA Splicing / genetics*
  • Sulfonamides / pharmacology
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology


  • Antigens, Neoplasm
  • Epitopes
  • Ethylenediamines
  • Histocompatibility Antigens Class I
  • Immune Checkpoint Inhibitors
  • MS023 compound
  • N-(3-chloro-7-indolyl)-1,4-benzenedisulphonamide
  • Peptides
  • Protein Isoforms
  • Pyrroles
  • Sulfonamides