Tumour-wide RNA splicing aberrations generate actionable public neoantigens

Area of Science:

• Immunology and Oncology
• Molecular Biology
• Cancer Genomics

Background:

• T cell-based immunotherapies show promise for cancer treatment by targeting cancer-specific antigens.
• Efficacy is often limited by low somatic mutation rates and significant intratumoural heterogeneity in tumors.

Purpose of the Study:

• To identify and characterize a novel class of tumour-wide public neoantigens arising from RNA splicing aberrations.
• To evaluate the potential of these neoantigens for T cell-based cancer immunotherapy.

Main Methods:

• Identification of T cell receptor clones targeting neoantigens from aberrant RNA splicing (GNAS and RPL22).
• Analysis of multi-site tumour biopsies to confirm tumour-wide expression of specific neojunctions (e.g., GNAS).
• Assessment of neoantigen-specific CD8+ T cell responses against cancer cells.

Main Results:

• Discovery of a previously uncharacterized class of tumour-wide public neoantigens derived from RNA splicing aberrations.
• Demonstration that GNAS neojunctions are expressed tumour-wide in glioma, mesothelioma, prostate, and liver cancers.
• Confirmation that these endogenously generated neoantigens can trigger cancer cell eradication by CD8+ T cells.

Conclusions:

• Aberrant RNA splicing generates tumour-wide neoantigens that are recognized by T cells.
• Dysregulated splicing factor expression contributes to recurrent neojunction upregulation in specific cancers.
• These findings provide a molecular basis for developing T cell immunotherapies to address intratumoural heterogeneity.