Targeting SALL4 with an HLA Class I–Restricted TCR for Cancer Immunotherapy

Aberrant expression of the oncogene SALL4 is associated with stemness, a more aggressive cancer phenotype, and reduced patient survival in various tumor types, making SALL4 a potential target for cancer immunotherapy. We conducted a transcriptional analysis of SALL4 expression in colorectal cancer tissues and demonstrated that SALL4 was overexpressed in primary tumors and paired liver metastases. Then, we identified the SALL4-derived S9V peptide as a naturally processed peptide that induced specific CD8+ T-cell responses from the peripheral blood of patients with gastrointestinal cancer, whereas no responses were observed in the peripheral blood of healthy donors. Thereafter, we isolated an SALL4-specific T-cell receptor (TCR) that recognized this peptide in the most common HLA molecule in the Caucasian population, HLA-A2, and used this to develop TCR-engineered T cells. In vitro analysis showed that SALL4 TCR-redirected primary CD8+ T cells exhibited cytotoxic effects against SALL4-expressing tumor cells and produced effector cytokines. In vivo, SALL4-TCR T cells significantly reduced tumor growth and improved the survival of tumor-bearing mice. Moreover, SALL4-TCR T cells displayed no toxicity against hematopoietic stem cells. Thus, we conclude that T cells engineered to express a SALL4-specific TCR have the potential to be effective as immunotherapy for solid cancers and pave the way for further clinical development.

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Publication Details

Journal
Cancer Immunology Research
Published
2025-10-20
DOI
https://doi.org/10.1158/2326-6066.cir-24-0207
Primary Topic
Renal and related cancers
Type
article
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article

Targeting SALL4 with an HLA Class I–Restricted TCR for Cancer Immunotherapy

Virginie Mougey, Francine Garnache‐Ottou, Myriam Ben Khelil, Marie Perchaud et al.
Cancer Immunology Research
Renal and related cancers
article

Targeting SALL4 with an HLA Class I–Restricted TCR for Cancer Immunotherapy

Virginie Mougey, Francine Garnache‐Ottou, Myriam Ben Khelil, Marie Perchaud, Romain Loyon, Maxime Fredon, Alexandre Harari, Adeline Bouard, Delphine Binda, Sara Bobisse, Olivier Adotévi, P. Guillaume, Camilla Jandus, Evan Seffar, Kamal Asgarov, Laurie Spehner, Angélique Vienot, Syrine Abdeljaoued, Marie Kroemer, Yann Godet, Mathieu Gonçalves-Venturelli, Charles-Frédéric Mantion, Christophe Borg, N. Adib, Marjorie Labesse
article en

Abstract

Aberrant expression of the oncogene SALL4 is associated with stemness, a more aggressive cancer phenotype, and reduced patient survival in various tumor types, making SALL4 a potential target for cancer immunotherapy. We conducted a transcriptional analysis of SALL4 expression in colorectal cancer tissues and demonstrated that SALL4 was overexpressed in primary tumors and paired liver metastases. Then, we identified the SALL4-derived S9V peptide as a naturally processed peptide that induced specific CD8+ T-cell responses from the peripheral blood of patients with gastrointestinal cancer, whereas no responses were observed in the peripheral blood of healthy donors. Thereafter, we isolated an SALL4-specific T-cell receptor (TCR) that recognized this peptide in the most common HLA molecule in the Caucasian population, HLA-A2, and used this to develop TCR-engineered T cells. In vitro analysis showed that SALL4 TCR-redirected primary CD8+ T cells exhibited cytotoxic effects against SALL4-expressing tumor cells and produced effector cytokines. In vivo, SALL4-TCR T cells significantly reduced tumor growth and improved the survival of tumor-bearing mice. Moreover, SALL4-TCR T cells displayed no toxicity against hematopoietic stem cells. Thus, we conclude that T cells engineered to express a SALL4-specific TCR have the potential to be effective as immunotherapy for solid cancers and pave the way for further clinical development.

Cancer Immunology ResearchVol. 14(1)
University of Geneva (CH), Memorial Sloan Kettering Cancer Center (US), Inserm (FR), Institut Pasteur (FR), Institut Gustave Roussy (FR), Unit of Virus Host Cell Interactions (FR), Centre Hospitalier Universitaire Vaudois (CH), Centre Hospitalier Universitaire de Besançon (FR), Methodology and Quality of Life Unit in Oncology (FR), University Hospital of Geneva (CH), Ludwig Cancer Research (CH), Université Bourgogne Franche-Comté (FR), Université Marie et Louis Pasteur (FR), Université de Franche-Comté (FR), University of Lausanne (CH)
Openalex Percentile: Top 74%
Renal and related cancers
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