Cell
Volume 184, Issue 15, 22 July 2021, Pages 4032-4047.e31
Journal home page for Cell

Article
Pharmacologic modulation of RNA splicing enhances anti-tumor immunity

https://doi.org/10.1016/j.cell.2021.05.038Get rights and content
Under an Elsevier user license
open archive

Highlights

  • Pharmacologic modulation of splicing enhances immune checkpoint blockade efficacy

  • RBM39 degradation and type I PRMT inhibition are well tolerated by immune cells

  • Splicing perturbation induces splicing-derived neoepitopes that are immunogenic

  • Rigorous framework for the identification of splicing-derived antigenic peptides

Summary

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

immune checkpoint blockade
immunotherapy
neoantigens
neoepitopes
immunopeptidome
PD1
PRMTs
RBM39
RNA splicing
splicing

Cited by (0)

15

These authors contributed equally

16

Lead contact