Neoantigen-targeted CD8⁺ T cell responses with PD-1 blockade therapy

Area of Science:

• Immunology
• Oncology
• Genetics

Background:

• Neoantigens, derived from mutations and presented by human leukocyte antigens (HLAs), are recognized by anti-tumor T cells.
• Studying neoantigen-specific T cell responses is challenging due to HLA diversity and limited clinical samples.

Purpose of the Study:

• To investigate the landscape of neoantigen-targeted T cell responses in patients with metastatic melanoma undergoing anti-programmed death receptor-1 (PD-1) immunotherapy.
• To identify characteristics of T cell responses associated with effective immunotherapy.

Main Methods:

• Applied novel technologies to capture neoantigen-specific T cells and clone their T cell receptors (neoTCRs) from patient blood and tumors.
• Generated personalized neoantigen-HLA capture reagents for single-cell isolation.
• Utilized CRISPR-Cas9 gene editing to reconstitute neoTCRs in donor T cells.

Main Results:

• Polyclonal T cell clonotypes recognizing a limited set of mutations were identified in patients with long-lasting responses to anti-PD-1 therapy.
• These neoTCR clonotypes were recurrently detected over time in both blood and tumor samples.
• Patients with no response showed neoantigen-specific T cell responses but with lower TCR polyclonality and lack of recurrence.

Conclusions:

• Effective anti-PD-1 immunotherapy correlates with the presence of polyclonal CD8+ T cells targeting immunodominant mutations.
• These T cells exhibit specific recognition and cytotoxicity, as demonstrated by gene editing experiments.
• Recurrent recognition of neoantigens by T cells over time is a hallmark of successful immunotherapy.