Abstract
Although chimeric antigen receptor (CAR)-T cells are promising effector cells to treat hematologic tumors, developing effective CAR-T cells for solid tumors remains challenging. Dickkopf-1 (DKK1) protein is widely expressed by human hematologic and solid tumors. Using the sequence of murine or humanized monoclonal antibody recognizing DKK1-A2 complexes (DKK1-P20 peptide in the context of HLA-A*0201) that are detected on all examined HLA-A2+ tumor samples but not normal tissues except tonsils, we generate DKK1-A2 CAR-T cells that specifically and effectively lyse HLA-A2- and DKK1-expressing tumor cells but not blood or bone marrow cells from HLA-A2+ healthy donors. In xenograft models of human myeloma, pancreatic, lung, and breast cancers and patient-derived xenograft of pancreatic cancer, DKK1-A2 but not CD19 CAR-T cells effectively control or eradicate established tumors without detectable toxicities in NSG or human DKK1 and HLA-A2-trangenic mice. This study indicates that DKK1-A2 CAR-T cells may be used to treat human cancers.
Data availability
This paper does not report any sequencing or proteomics data. Other previous published patient datasets used in the study can get access with the following accession numbers: GSE13591, GSE2350, GSE13159, GSE16515, GSE10072, EGAS00000000083 and GEPIA2. All the other data supporting the findings of this study are available with in the article, supplementary information and source files. Source data are provided with this paper.
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Acknowledgements
This work was supported by Startup Support from Houston Methodist Research Institute, Houston Methodist Hospital, by Cancer Prevention & Research Institute of Texas Recruitment of Established Investigator Award (RR180044) and High-Impact/High-Risk Research Award (RP210868), and by Leukemia and Lymphoma Society Translational Award (#6682-24) to Q.Y. Q.Y. and his research group were also supported by NCI R01s (CA239255, CA282099, CA278787, CA2855209, and CA285203 to Q.Y.). The authors thank the Houston Methodist Research Institute Research Pathology Core for histological studies, the Comparative Medicine Program for supporting animal studies, and the Flow Cytometry Core for flow cytometry studies.
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Conceptualization, Q.Y., J.Q., W.X., and Y.Z.; Methodology, Y.Z., W.X., J.Q., and Q.Y.; Investigation, Y.Z., W.X., J.Q., R.D., Q.G., Q.W., L.Z., W.W., C.Z., Y.L., L.X., and M.X.; Writing: Y.Z., W.X., and Q.Y.; Funding acquisition, Q.Y.; Resources, J.Q. and Q.Y.; Clinical collaborators: J.C.C. and N.F.E.; Critical reading and suggestion: Y.L., N.F.E., L.Z., and J.C.C.; Supervision: J.Q. and Q.Y.
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J.Q., W.X., and Q.Y. are inventors on patents in the field of DKK1-A2 targeted Therapies. The remaining authors declare no competing financial interests.
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Zhang, Y., Xiong, W., Qian, J. et al. T cells engineered against Dickkopf-1-A2 complex can be used to treat HLA-A2+ solid and hematologic cancers. Nat Commun (2026). https://doi.org/10.1038/s41467-026-69621-8
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DOI: https://doi.org/10.1038/s41467-026-69621-8
