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Identification of a naturally processed HLA-A*02:01-restricted CTL epitope from the human tumor-associated antigen
Marc Lopez1, Abderrezak Ghidouche2, Caroline Rochas2
1Inserm U1068, Centre de Recherche en Cancérologie de Marseille (CRCM), Equipe Oncologie Moléculaire, UM 105, Institut Paoli-Calmettes, CNRS, UMR7258, Aix-Marseille University, Marseille, France.
Abstract:
Nectin-4 is a tumor antigen present on the surface of breast, ovarian and lung carcinoma cells. It is rarely present in normal adult tissues and is therefore a candidate target for cancer immunotherapy. Here, we identified a Nectin-4 antigenic peptide that is naturally presented to T cells by HLA-A2 molecules. We first screened the 502 nonamer peptides of Nectin-4 (510 amino acids) for binding to and off-rate from eight different HLA class I molecules. We then combined biochemical, cellular and algorithmic assays to select 5 Nectin-4 peptides that bound to HLA-A*02:01 molecules. Cytolytic T lymphocytes were obtained from healthy donors, that specifically lyzed HLA-A2(+) cells pulsed with 2 out of the 5 peptides, indicating the presence of anti-Nectin-4 CD8(+) T lymphocytes in the human T cell repertoire. Finally, an HLA-A2-restricted cytolytic T cell clone derived from a breast cancer patient recognized peptide Nectin-4145-153 (VLVPPLPSL) and lyzed HLA-A2(+) Nectin-4(+) breast carcinoma cells. These results indicate that peptide Nectin-4145-153 is naturally processed for recognition by T cells on HLA-A2 molecules. It could be used to monitor antitumor T cell responses or to immunize breast cancer patients.
Insights
Researchers identified a Nectin-4 peptide (Nectin-4145-153) that cancer immunotherapies can target. This peptide is presented by HLA-A2 molecules on cancer cells, offering a potential strategy for monitoring or inducing anti-tumor T cell responses.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Nectin-4 is a tumor antigen found on various carcinoma cells, making it a potential target for cancer immunotherapy.
- Its limited expression in normal tissues enhances its suitability as a therapeutic target.
Purpose of the Study:
- To identify Nectin-4 antigenic peptides naturally presented by HLA-A2 molecules for cancer immunotherapy.
- To evaluate the potential of these peptides in monitoring or inducing anti-tumor T cell responses.
Main Methods:
- Screening of Nectin-4 nonamer peptides for binding and off-rate to HLA class I molecules.
- Biochemical, cellular, and algorithmic assays to select peptides binding to HLA-A*02:01.
- Generation of cytolytic T lymphocytes (CTLs) from healthy donors and a breast cancer patient.
Main Results:
- Five Nectin-4 peptides were identified that bind to HLA-A*02:01.
- CTLs from healthy donors recognized Nectin-4 peptides presented by HLA-A2+ cells.
- A breast cancer patient's CTL clone recognized Nectin-4145-153 (VLVPPLPSL) on HLA-A2+ Nectin-4+ breast carcinoma cells.
Conclusions:
- Peptide Nectin-4145-153 is naturally processed and presented by HLA-A2 molecules on cancer cells.
- This peptide holds potential for monitoring anti-tumor T cell responses or for use in cancer immunizations.
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