Pharmacologic modulation of RNA splicing enhances anti-tumor immunity

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Mutations in DNA are known sources of neoantigens that influence response to immune checkpoint blockade.
• Alterations in RNA splicing in cancer cells can also produce neoepitopes, but their antigenicity and clinical potential remain largely unexplored.

Purpose of the Study:

• To investigate if pharmacologic splicing modulation can generate neoantigens.
• To determine if splicing modulation can elicit anti-tumor immunity and enhance checkpoint immunotherapy.

Main Methods:

• Pharmacologic modulation of RNA splicing using specific drug classes.
• Assessment of tumor growth inhibition and anti-tumor immunity in vivo.
• Analysis of T cell dependency and peptide presentation on MHC class I.
• Characterization of splicing changes and the immunopeptidome.

Main Results:

• Splicing modulation generated bona fide neoantigens and elicited anti-tumor immunity.
• This approach inhibited tumor growth and augmented checkpoint blockade efficacy.
• The effects were dependent on host T cells and peptides presented on tumor MHC class I.
• Stereotyped splicing changes across tumor types altered the MHC I-bound immunopeptidome, yielding immunogenic splicing-derived neoepitopes.

Conclusions:

• Splicing modulation is an untapped source of immunogenic peptides.
• This strategy can enhance responses to immune checkpoint blockade.
• Splicing modulation is a clinically translatable approach to improve cancer immunotherapy.