Khelil et al. demonstrated that SALL4 is overexpressed in multiple tumor types, including primary colorectal cancers and paired liver metastasis, but is silenced in almost all adult tissues. The SALL4-derived S9V peptide was restricted by HLA-A2, and induced specific CD8+ T cell responses from the peripheral blood of patients with GI cancers. In vitro, SALL4-S9V-specific TCR-engineered CD8+ T cells were cytotoxic against SALL4-expressing tumor cells, but didn’t recognize hematopoietic stem cells (HSC). Adoptively transferred SALL4-S9V-specific TCR T cells suppressed tumor growth and improved survival in SALL4+ MDA-MB231 xenografts, without affecting HSCs.
Contributed by Shishir Pant
ABSTRACT: Aberrant expression of the oncogene SALL4 is associated with stemness, 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 (CRC) tissues and demonstrated that SALL4 was overexpressed in primary tumor and paired liver metastasis. 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 gastrointestinal cancer patients whereas no responses were observed for the peripheral blood of healthy donors. Thereafter, we isolated a 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 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.
Author Info: (1) Institut Gustave Roussy, Villejuif, France. (2) INSERM, EFS BFC, UMR1098-RIGHT, University of Franche-Comte, Besançon, France, Besançon, Bourgogne-Franche-Comte, France. (3) Un
Author Info: (1) Institut Gustave Roussy, Villejuif, France. (2) INSERM, EFS BFC, UMR1098-RIGHT, University of Franche-Comte, Besançon, France, Besançon, Bourgogne-Franche-Comte, France. (3) Université Bourgogne Franche-Comté, EFS, INSERM, UMR RIGHT, F-25000 Besançon, France, Besançon, France. (4) Université Bourgogne Franche-Comté, France. (5) Université Bourgogne Franche-Comté, EFS, INSERM, UMR RIGHT, F-25000 Besançon, France, Besançon, France. (6) Université de Franche-Comté, EFS, INSERM, UMR RIGHT, F-25000 Besançon, France, Besançon, France. (7) Université Marie et Louis Pasteur, EFS, INSERM UMR1098 RIGHT, Besançon, F-25000, France, Besançon, Bourgogne-Franche-Comte, France. (8) Université Bourgogne Franche-Comté, France. (9) University of Lausanne, Lausanne, Switzerland. (10) Interactions Hte-Greffon-Tumeur & Ingénierie Cellulaire et Génique, Besançon, France. (11) Memorial Sloan Kettering Cancer Center, France. (12) Université de Franche-Comté, EFS, INSERM, UMR RIGHT, F-25000 Besançon, France, Besançon, France. (13) University Hospital of Besançon, Besançon, France. (14) EFS-BFC, Besançon, France. (15) Université de Franche-Comté, EFS, INSERM, UMR RIGHT, F-25000 Besançon, France, Besançon, Bourgogne-Franche-Comté, France. (16) Ludwig Institute for Cancer Research and Department of Oncology, University of Lausanne, Lausanne, Switzerland. (17) University Hospital of Lausanne, Lausanne, Switzerland. (18) University of Geneva, Geneva, Switzerland. (19) Université de Franche-Comté, CHU Besançon, EFS, INSERM, UMR RIGHT, F-25000 Besan̤on, France, Besançon, France. (20) INSERM CIC-1431, Clinical Investigation Center in Biotherapy, University Hospital of Besançon, F-25000 Besançon, France, France. (21) INSERM, UMR1098, Besançon cedex, France. (22) University of Franche-Comté, Besançon, France. (23) University Hospital of Besançon, France. (24) university hospital of Besançon, Besançon, France. (25)Université de Franche-Comté, EFS, INSERM, UMR RIGHT, F-25000 Besançon, France, Besançon, France.
