PLAC1-specific TCR-engineered T cells mediate antigen-specific antitumor effects in breast cancer

  • Authors:
    • Qiongshu Li
    • Muyun Liu
    • Man Wu
    • Xin Zhou
    • Shaobin Wang
    • Yuan Hu
    • Youfu Wang
    • Yixin He
    • Xiaoping Zeng
    • Junhui Chen
    • Qubo Liu
    • Dong Xiao
    • Xiang Hu
    • Weibin Liu
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  • Published online on: February 16, 2018     https://doi.org/10.3892/ol.2018.8075
  • Pages: 5924-5932
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Abstract

Placenta-specific 1 (PLAC1), a novel cancer-testis antigen (CTA), is expressed in a number of different human malignancies. It is frequently produced in breast cancer, serving a function in tumorigenesis. Adoptive immunotherapy using T cell receptor (TCR)‑engineered T cells against CTA mediates objective tumor regression; however, to the best of our knowledge, targeting PLAC1 using engineered T cells has not yet been attempted. In the present study, the cDNAs encoding TCRα‑ and β‑chains specific for human leukocyte antigen (HLA)‑A*0201‑restricted PLAC1 were cloned from a cytotoxic T‑lymphocyte, generated by in vitro by the stimulation of CD8+ T cells using autologous HLA‑A2+ dendritic cells loaded with a PLAC1‑specific peptide (p28‑36, VLCSIDWFM). The TCRα/β‑chains were linked by a 2A peptide linker (TCRα‑Thosea asigna virus‑TCRβ), and the constructs were cloned into the lentiviral vector, followed by transduction into human cytotoxic (CD8+) T cells. The efficiency of transduction was up to 25.16%, as detected by PLAC1 multimers. TCR‑transduced CD8+ T cells, co‑cultured with human non‑metastatic breast cancer MCF‑7 cells (PLAC1+, HLA‑A2+) and triple‑negative breast cancer MDAMB‑231 cells (PLAC1+, HLA‑A2+), produced interferon γ and tumor necrosis factor α, suggesting TCR activation. Furthermore, the PLAC1 TCR‑transduced CD8+ T cells efficiently and specifically identified and annihilated the HLA‑A2+/PLAC1+ breast cancer cell lines in a lactate dehydrogenase activity assay. Western blot analysis demonstrated that TCR transduction stimulated the production of mitogen‑activated protein kinase signaling molecules, extracellular signal‑regulated kinases 1/2 and nuclear factor‑κB, through phosphoinositide 3‑kinase γ‑mediated phosphorylation of protein kinase B in CD8+ T cells. Xenograft mouse assays revealed that PLAC1 TCR‑transduced CD8+T cells significantly delayed the tumor progression in mice‑bearing breast cancer compared with normal saline or negative control‑transduced groups. In conclusion, a novel HLA‑A2‑restricted and PLAC1‑specific TCR was identified. The present study demonstrated PLAC1 to be a potential target for breast cancer treatment; and the usage of PLAC1‑specific TCR‑engineered T cells may be a novel strategy for PLAC1-positive breast cancer treatment.
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April-2018
Volume 15 Issue 4

Print ISSN: 1792-1074
Online ISSN:1792-1082

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Spandidos Publications style
Li Q, Liu M, Wu M, Zhou X, Wang S, Hu Y, Wang Y, He Y, Zeng X, Chen J, Chen J, et al: PLAC1-specific TCR-engineered T cells mediate antigen-specific antitumor effects in breast cancer. Oncol Lett 15: 5924-5932, 2018
APA
Li, Q., Liu, M., Wu, M., Zhou, X., Wang, S., Hu, Y. ... Liu, W. (2018). PLAC1-specific TCR-engineered T cells mediate antigen-specific antitumor effects in breast cancer. Oncology Letters, 15, 5924-5932. https://doi.org/10.3892/ol.2018.8075
MLA
Li, Q., Liu, M., Wu, M., Zhou, X., Wang, S., Hu, Y., Wang, Y., He, Y., Zeng, X., Chen, J., Liu, Q., Xiao, D., Hu, X., Liu, W."PLAC1-specific TCR-engineered T cells mediate antigen-specific antitumor effects in breast cancer". Oncology Letters 15.4 (2018): 5924-5932.
Chicago
Li, Q., Liu, M., Wu, M., Zhou, X., Wang, S., Hu, Y., Wang, Y., He, Y., Zeng, X., Chen, J., Liu, Q., Xiao, D., Hu, X., Liu, W."PLAC1-specific TCR-engineered T cells mediate antigen-specific antitumor effects in breast cancer". Oncology Letters 15, no. 4 (2018): 5924-5932. https://doi.org/10.3892/ol.2018.8075