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Phosphorylated vimentin as an immunotherapeutic target against metastatic colorectal cancer

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Abstract

Colorectal cancer (CRC) patients with metastatic lesions have low 5-year survival rates. During metastasis, cancer cells often obtain unique characteristics such as epithelial–mesenchymal transition (EMT). Vimentin a biomarker contributes to EMT by changing cell shape and motility. Since abnormal phosphorylation is a hallmark of malignancy, targeting phosphorylated vimentin is a feasible approach for the treatment of metastatic tumors while sparing non-tumor cells. Recent evidence has revealed that both CD8 cytotoxic T lymphocytes (CTLs) and also CD4 helper T lymphocytes (HTLs) can distinguish post-translationally modified antigens from normal antigens. Here, we showed that the expression of phosphorylated vimentin was upregulated in metastatic sites of CRC. We also showed that a chemotherapeutic reagent augmented the expression of phosphorylated vimentin. The novel phosphorylated helper peptide epitopes from vimentin could elicit a sufficient T cell response. Notably, precursor lymphocytes that specifically reacted to these phosphorylated vimentin-derived peptides were detected in CRC patients. These results suggest that immunotherapy targeting phosphorylated vimentin could be promising for metastatic CRC patients.

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Abbreviations

APCs:

Antigen-presenting cells

CRC:

Colorectal cancer

CTLs:

CD8 cytotoxic T lymphocytes

DCs:

Dendritic cells

EMT:

Epithelial–mesenchymal transition

HTLs:

CD4 helper T lymphocytes

L-cells:

Fibroblast cell lines

mAb:

Monoclonal antibody

PBMCs:

Peripheral blood mononuclear cells

SCC:

Squamous cell carcinoma

TAA:

Tumor-associated antigen

TCR:

T cell receptors

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Funding

This work was supported by the Japanese Society for the Promotion of Science (JSPS) KAKENHI Grant Numbers 17K16884 and 19K07452.

Author information

Authors and Affiliations

  1. Department of Pathology, Asahikawa Medical University, 2-1-1-1, Midorigaoka-Higashi, Asahikawa, 0788510, Japan

    Mizuho Ohara, Kenzo Ohara, Takumi Kumai, Takayuki Ohkuri, Toshihiro Nagato, Yui Hirata-Nozaki, Akemi Kosaka, Marino Nagata, Ryusuke Hayashi, Shohei Harabuchi, Yuki Yajima, Kensuke Oikawa & Hiroya Kobayashi

  2. Department of Otolaryngology-Head and Neck surgery, Asahikawa Medical University, Asahikawa, Japan

    Kenzo Ohara, Takumi Kumai, Yui Hirata-Nozaki, Ryusuke Hayashi, Shohei Harabuchi & Yasuaki Harabuchi

  3. Department of Innovative Head and Neck Cancer Research and Treatment (IHNCRT), Asahikawa Medical University, 2-1-1-1, Midorigaoka-Higashi, Asahikawa, 0788510, Japan

    Takumi Kumai

  4. Department of Surgery, Asahikawa Medical University, Asahikawa, Japan

    Mizuho Ohara, Yasuo Sumi & Hiroyuki Furukawa

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  1. Mizuho Ohara
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Contributions

MO, KO, TN, and YH-N contributed to data acquisition. AK, MN, RH, SH, and YY contributed to data acquisition and analysis. TK, TO, and KO contributed to the design and concept and drafting of the manuscript. All authors were involved in data interpretation, preparation, and review of the manuscript draft and approved the final manuscript version for submission.

Corresponding authors

Correspondence to Takumi Kumai or Takayuki Ohkuri.

Ethics declarations

Conflicts of interest

The authors declare that they have no conflict of interest.

Ethical approval and ethical standards

This study followed the principles of the Helsinki Declaration, and the study protocol was approved by the Asahikawa Medical University Institutional Ethics Committee (approval number #16040-3).

Informed consent

All blood samples from healthy human volunteers and CRC patients (Asahikawa Medical University Hospital, 2016-2018) were obtained after obtaining written informed consent (Institutional Ethics Committee approval number #16040-3). The patients and healthy donors agreed to the use of their specimens and data for research and publication.

Cell line authentication

The CRC cell lines SW480 and SW620 were purchased from KAC Co., Ltd. (Kyoto, Japan). Lung SCC cell lines Calu-1 and Jurkat (T cell lymphoma) were obtained from the American Type Culture Collection (ATCC, Manassas, VA). The gingival SCC cell line Sa-3 and lung large cell carcinoma cell line Lu65 were supplied by the RIKEN Bio-Resource Center (Tsukuba, Japan). The renal cell carcinoma cell line SW839 was obtained from the Cell Resource Center for Biomedical Research Institute of Development (Aging and Cancer, Tohoku University, Sendai, Japan). Cell authentication assays were performed by each company, and the cell passaging was no more than five times.

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Mizuho Ohara and Kenzo Ohara have first authorship.

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Ohara, M., Ohara, K., Kumai, T. et al. Phosphorylated vimentin as an immunotherapeutic target against metastatic colorectal cancer. Cancer Immunol Immunother 69, 989–999 (2020). https://doi.org/10.1007/s00262-020-02524-9

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