Mis-splicing-derived neoantigens and cognate TCRs in splicing factor mutant leukemias

Area of Science:

• Oncology
• Immunology
• Molecular Biology
• Cancer Genomics

Background:

• Somatic mutations in RNA splicing factors are common in cancers, leading to aberrant mRNA isoforms.
• These splicing alterations can generate unique tumor neoantigens, which are targets for the immune system.
• Understanding these neoantigens is crucial for developing targeted cancer immunotherapies.

Purpose of the Study:

• To identify neoantigens derived from recurrent RNA splicing alterations in myeloid malignancies.
• To isolate and characterize T cell receptors (TCRs) reactive to these splicing-derived neoantigens.
• To evaluate the potential of TCR-engineered T cells for targeting leukemia with specific splicing mutations.

Main Methods:

• Utilized feature-barcoded peptide-major histocompatibility complex (MHC) dextramers for neoantigen-reactive TCR isolation.
• Collected samples from healthy donors, patients with active myeloid malignancy, and post-allogeneic stem cell transplant.
• Engineered T cells with identified TCRs and assessed their recognition and cytotoxic activity against cancer cells.

Main Results:

• Identified bona fide neoantigens translated from stereotyped splicing alterations driven by leukemia-associated mutations.
• Detected neoantigen-reactive CD8+ T cells in patients with active myeloid malignancy, exhibiting impaired cytotoxic function.
• T cells engineered with TCRs targeting SRSF2 mutant-induced neoantigens demonstrated specific recognition and cytotoxicity of SRSF2-mutant leukemia.

Conclusions:

• Recurrent RNA mis-splicing events serve as a source of actionable public neoantigens in myeloid leukemias.
• These findings provide proof of concept for genetically redirecting T cells to target neoantigens arising from RNA splicing alterations.
• This approach holds promise for novel immunotherapeutic strategies against cancers with splicing factor mutations.