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

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Aberrant SALL4 oncogene expression correlates with cancer stemness, aggressive phenotypes, and poor patient survival.
• SALL4 overexpression is observed in colorectal cancer tissues, including primary tumors and liver metastases.

Purpose of the Study:

• To investigate SALL4 as a therapeutic target for cancer immunotherapy.
• To develop and evaluate SALL4-specific T-cell receptor (TCR)-engineered T cells for solid cancer treatment.

Main Methods:

• Transcriptional analysis of SALL4 expression in colorectal cancer.
• Identification of a SALL4-derived peptide (S9V) inducing CD8+ T-cell responses.
• Isolation of an SALL4-specific TCR recognizing the S9V peptide in HLA-A2.
• Development of TCR-engineered T cells and in vitro/in vivo efficacy and toxicity assessments.

Main Results:

• SALL4 was overexpressed in colorectal cancer tissues and metastases.
• The S9V peptide elicited specific CD8+ T-cell responses in cancer patients but not healthy donors.
• SALL4-TCR T cells demonstrated in vitro cytotoxicity against SALL4-expressing tumor cells and in vivo tumor growth reduction.
• SALL4-TCR T cells showed no toxicity against hematopoietic stem cells.

Conclusions:

• T cells engineered with a SALL4-specific TCR are a potential immunotherapy for solid cancers.
• This approach warrants further clinical development for treating various solid tumors.