Engineered CD4 TCR T cells with conserved high-affinity TCRs targeting NY-ESO-1 for advanced cellular therapies in cancer
While cancer immunotherapy has primarily focused on CD8 T cells, CD4 T cells are increasingly recognized for their role in antitumor immunity. The <i>HLA-DRB3*02:02</i> allele is found in 50% of Caucasians. In this study, we screened <i>HLA-DRB3*02:02</i> patients with melanoma for tumor-specific CD4 T cells and identified robust New York esophageal squamous cell carcinoma 1 (NY-ESO-1)<sub>123-137</sub>/<i>HLA-DRB3*02:02</i> CD4 T cell activity in both peripheral blood and tumor tissue. By analyzing NY-ESO-1<sub>123-137</sub>/<i>HLA-DRB3*02:02</i>-restricted CD4 T cell clones, we uncovered an unexpectedly high cytotoxicity, strong T helper 1 polarization, and recurrent αβ T cell receptor (TCRαβ) usage across patients and anatomical sites. These responses were also present in other NY-ESO-1-expressing cancers. TCRs from these clones, when transduced into primary CD4 T cells, showed direct antitumor efficacy both in vitro and in vivo. Our findings suggest that these TCRs are promising for adoptive T cell transfer therapy, enabling broader targeting of NY-ESO-1-expressing adult and pediatric cancers in clinical settings.
Authors
- Philippe Guillaume (ORCID: https://orcid.org/0000-0002-6340-0963)
- Lise Queiroz
- Olivier Michielin (ORCID: https://orcid.org/0000-0003-4926-6355)
- David Gfeller (ORCID: https://orcid.org/0000-0002-3952-0930)
- George Coukos (ORCID: https://orcid.org/0000-0001-8813-7367)
- Francesco Ceppi (ORCID: https://orcid.org/0000-0002-9665-3190)
- Patrick Reichenbach
- Raffaele Renella (ORCID: https://orcid.org/0000-0002-5041-2308)
- Mara Cenerenti (ORCID: https://orcid.org/0000-0001-6630-0557)
- Jean‐Paul Rivals (ORCID: https://orcid.org/0000-0002-5525-1435)
- Julien Schmidt (ORCID: https://orcid.org/0000-0003-3034-6857)
- Alexandre Harari (ORCID: https://orcid.org/0000-0002-1055-2090)
- Melita Irving (ORCID: https://orcid.org/0000-0002-6849-7194)
- Raphaël Genolet (ORCID: https://orcid.org/0000-0001-9335-3945)
- Ziyang Su
- Margaux Saillard (ORCID: https://orcid.org/0000-0001-9467-1830)
- Vincent Zoete (ORCID: https://orcid.org/0000-0002-2336-6537)
- Julien Racle (ORCID: https://orcid.org/0000-0002-0100-0323)
- Olivier Adotévi (ORCID: https://orcid.org/0000-0002-7742-136X)
- Camilla Jandus (ORCID: https://orcid.org/0000-0002-7405-5747)
- Daniel E. Speiser (ORCID: https://orcid.org/0000-0003-2031-3250)
- Julien Cesbron
- Jean Villard (ORCID: https://orcid.org/0000-0003-2667-7506)
- Morteza Hafezi (ORCID: https://orcid.org/0009-0005-2494-449X)
- Pedro Romero (ORCID: https://orcid.org/0000-0002-9688-2882)
Institutions
- University of Geneva (CH)
- SIB Swiss Institute of Bioinformatics (CH)
- Inserm (FR)
- University Hospital of Geneva (CH)
- Ludwig Cancer Research (CH)
- Université Bourgogne Franche-Comté (FR)
- Mother Hospital (IN)
- University of Lausanne (CH)
Publication Details
- Journal
- Science Advances
- Published
- 2025-06-27
- DOI
- https://doi.org/10.1126/sciadv.adu5754
- Citations
- 3
- Primary Topic
- CAR-T cell therapy research
- Type
- article
- Field-Weighted Citation Impact
- 3.14
Funders
- Institute of Genetics and Genomics of Geneva