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Low-dose gemcitabine induces major histocompatibility complex class I-related chain A/B expression and enhances an antitumor innate immune response in pancreatic cancer

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Abstract

We investigated the effect of gemcitabine (GEM), a key drug for pancreatic cancer treatment, on the expression of cell surface MICA/B in pancreatic cancer cells and resulting cytotoxicity of γδ T cells. We assessed the effect of GEM on the upregulation of cell surface MICA/B expression by flow cytometry, utilizing six pancreatic cancer cell lines. MICA and CD16 expressions from resected pancreatic cancer patient specimens, which received neoadjuvant chemotherapy (NAC) with GEM, were analyzed by immunohistochemistry. GEM could increase MICA/B expression on cell surface in pancreatic cancer cell lines (in 2 of 6 cell lines). This effect was most effectively at concentration not affecting cell growth of GEM (0.001 μM), because MICA/B negative population was appeared at concentration at cytostatic and cytotoxic effect to cell growth (0.1 and 10 μM). The cytotoxic activity of γδ T cells against PANC-1 was detected and functions through interactions between NKG2D and MICA/B. However, the enhancement of NKG2D-dependent cytotoxicity with increased MICA/B expression, by GEM treatment, was not observed. In addition, soluble MIC molecules were released from pancreatic cancer cell lines in culture supernatant with GEM treatment. Immunohistochemical staining demonstrated that MICA expression in tumor cells and CD16 positive cells surrounding tumors were significantly higher in the NAC group compared to that of the control group. There was a significant correlation between NAC and MICA expression, as well as NAC and CD16 positive cell expression. The present results indicate that low-dose GEM-induced MICA/B expression enhances innate immune function rather than cytotoxicity in pancreatic cancer. In addition, our result suggests that the inhibition of cleavage and release of MIC molecules from the tumor surface could potentially improve NKG2D-dependent cytotoxicity.

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Abbreviations

ADAM:

A disintegrin and metalloprotease

γδ:

Gamma delta

GEM:

Gemcitabine

KIRs:

Killer cell immunoglobulin-like receptors

MICA/B:

Major histocompatibility complex class 1-related chain A/B

MDSCs:

Myeloid-derived suppressor cells

NKG2D:

Natural killer, group 2, member D

NAC:

Neoadjuvant chemotherapy

NK:

Natural killer

TGF-β:

Transforming growth factor-β

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Acknowledgments

This work was supported by JSPS KAKENHI Grant Number 25462106.

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Authors and Affiliations

  1. Department of Gastroenterological Surgery, Kanazawa University Hospital, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8641, Japan

    Tomoharu Miyashita, Isamu Makino, Hisatoshi Nakagawara, Hidehiro Tajima, Hiroyuki Takamura, Hirohisa Kitagawa, Sachio Fushida & Tetsuo Ohta

  2. Medinet Medical Institute, MEDINET Co., Ltd., 2-2-8 Tamagawadai, Setagaya-ku, Tokyo, 158-0096, Japan

    Kenji Miki & Takashi Kamigaki

  3. Department of Surgery, Johns Hopkins University School of Medicine, 4940 Eastern Avenue, Baltimore, MD, 21224, USA

    Ali K. Ahmed, Mark D. Duncan & John W. Harmon

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  1. Tomoharu Miyashita
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Correspondence to Tomoharu Miyashita.

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Miyashita, T., Miki, K., Kamigaki, T. et al. Low-dose gemcitabine induces major histocompatibility complex class I-related chain A/B expression and enhances an antitumor innate immune response in pancreatic cancer. Clin Exp Med 17, 19–31 (2017). https://doi.org/10.1007/s10238-015-0394-x

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  • DOI: https://doi.org/10.1007/s10238-015-0394-x

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