Antigen Experienced T Cells from Peripheral Blood Recognize p53 Neoantigens

Area of Science:

• Immunology
• Oncology
• Molecular Biology

Background:

• The TP53 tumor suppressor gene is frequently mutated in various cancers.
• Neoantigens arising from TP53 mutations can elicit anti-tumor immune responses.
• Identifying T cells that recognize these neoantigens is crucial for developing effective cancer immunotherapies.

Purpose of the Study:

• To evaluate antigen-experienced T cells in peripheral blood lymphocytes (PBLs) for their reactivity to p53 neoantigens in cancer patients.
• To determine if PBLs can serve as a surrogate for tumor-infiltrating lymphocytes (TILs) in detecting p53 neoantigen-specific T-cell responses.
• To explore the potential of PBL-derived T cells for cancer cell therapy.

Main Methods:

• Peripheral blood lymphocytes (PBLs) were isolated from patients with TP53-mutated tumors.
• Antigen-experienced T cells were sorted and subjected to in vitro stimulation (IVS) with p53 neoantigens.
• Cultures were expanded using a rapid expansion protocol, and T-cell responses were assessed.
• T-cell receptor (TCR) sequencing was performed to track clonotypes and identify neoantigen-specific T cells.

Main Results:

• T-cell responses to p53 neoantigens were observed in PBLs of patients who also exhibited TIL responses to TP53 mutations, suggesting congruence between PBL and TIL reactivity.
• Specific CD4+ and CD8+ T-cell responses were detected against p53 neoantigens (p53R175H, p53Y220C, p53R248W), with high reactivity noted against p53R175H and HLA-A*02:01.
• TCR analysis confirmed the enrichment of p53 neoantigen-reactive T cells and identified shared and unique TCRs between PBLs and TILs.
• TP53 mutation-specific T cells recognized tumor cell lines expressing the relevant neoantigen and HLA restriction element.

Conclusions:

• Peripheral blood lymphocytes (PBLs) provide a noninvasive source of T cells targeting TP53 mutations.
• PBLs can serve as a valuable indicator of intratumoral p53 neoantigen immune responses.
• These findings support the use of PBL-derived T cells for therapeutic strategies against TP53-mutated cancers.