J Cancer 2021; 12(22):6629-6639. doi:10.7150/jca.62123 This issue

Research Paper

Synergistic killing effects of PD-L1-CAR T cells and colorectal cancer stem cell-dendritic cell vaccine-sensitized T cells in ALDH1-positive colorectal cancer stem cells

Liu Liu1*, Yuanyuan Liu1*, Yang Xia2*, Guanlong Wang1, Xiushan Zhang1, Huan Zhang3, Yang Xu1, Yuan Yuan1, Shangquan Liu1, Yi Wang1✉

1. The First People's Hospital of Hefei/The Third Affiliated Hospital of Anhui Medical University, Hefei 230061, P.R. China.
2. Taizhou People's Hospital/The Fifth Affiliated Hospital of Nantong University, Taizhou 225300, P.R. China.
3. Linquan County People's Hospital, Linquan 236400, P.R. China.
*These authors contribute equally to this work.

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Citation:
Liu L, Liu Y, Xia Y, Wang G, Zhang X, Zhang H, Xu Y, Yuan Y, Liu S, Wang Y. Synergistic killing effects of PD-L1-CAR T cells and colorectal cancer stem cell-dendritic cell vaccine-sensitized T cells in ALDH1-positive colorectal cancer stem cells. J Cancer 2021; 12(22):6629-6639. doi:10.7150/jca.62123. Available from https://www.jcancer.org/v12p6629.htm

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Abstract

Graphic abstract

Cancer stem cells (CSCs) are characterized by self-renewal and unlimited proliferation, providing a basis for tumor occurrence, metastasis, and recurrence. Because CSCs are highly resistant to conventional chemotherapy and radiotherapy, various immunotherapies, particularly chimeric antigen receptor T cell (CAR-T) therapy and dendritic cell (DC)-based vaccine therapy, are currently being developed. Accordingly, in this study, we evaluated programmed cell death ligand-1 (PD-L1) expression in colorectal CSCs (CCSCs) and non-CCSCs and designed a combination immunotherapy synchronously utilizing PD-L1-CAR-T cells together with CCSC-DC vaccine-sensitized T cells for the treatment of colorectal cancer. PD-L1-CAR-T cells specifically recognized the PD-L1 molecule on CCSCs by binding to the extracellular domain of programmed cell death-1. The CCSC-DC vaccine was prepared using CCSC lysates. We found that aldehyde dehydrogenase 1 (ALDH1)-positive CCSCs were abundant in samples from patient tumor tissues and cancer cell lines. Moreover, PD-L1 was highly expressed in ALDH1-positive CCSCs compared with that in non-CCSCs. Monotherapy with PD-L1-CAR-T cells or CCSC-DC vaccine only elicited moderate tumor remission both in vitro and in vivo. However, combination therapy markedly killed cancer cells and relieved the tumor burden in mice. Our findings may provide a novel strategy for the clinical treatment of colorectal malignancy.

Keywords: colorectal cancer stem cells, PD-L1-CAR T cells, colorectal cancer stem cell-dendritic cell vaccine, synergistic killing, ALDH1