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

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.