Tumor-wide RNA splicing aberrations generate immunogenic public neoantigens

Area of Science:

• Oncology
• Immunology
• Genomics

Background:

• T-cell immunotherapies face challenges due to heterogeneous cancer antigen expression within tumors.
• Cancer-specific splicing aberrations present a potential source for broadly applicable and uniformly expressed neoantigens.

Approach:

• Developed a novel computational pipeline to identify consistently expressed neojunctions across diverse cancer types.
• Analyzed neojunctions for recurrence across patients and assessed their expression patterns (intratumoral heterogeneity vs. tumor-wide).
• Identified CD8+ T-cell responses to neoantigens derived from tumor-wide and conserved neojunctions in GNAS and RPL22.

Key Points:

• Discovered recurrent neojunctions, some exhibiting intratumoral heterogeneity and others being tumor-wide.
• Identified specific CD8+ T-cell clones targeting neoantigens from GNAS and RPL22 neojunctions.
• Demonstrated that TCR-engineered T-cells targeting these neoantigens effectively eradicate tumor cells.

Conclusions:

• Cancer-specific splicing factor dysregulation drives recurrent neojunction expression.
• A subset of neojunctions are intratumorally conserved and public, offering a basis for novel immunotherapies.
• These findings provide a molecular strategy to overcome intratumoral heterogeneity in T-cell-based cancer treatments.