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Gemcitabine Induces Major Histocompatibility Complex Class I-Related Chain A/B Expression, Activating γδ T Cell Function in Pancreatic Cancer
Tomoharu Miyashita*1, 3, Kenji Miki2, John W. Harmon3, Ali K. Ahmed3, Hidehiro Tajima1, Sachio Fushida1, Tetsuo Ohta1
1Department of Gastroenterologic Surgery, Kanazawa University Hospital, Kanazawa, Japan; 2Medinet Medical Institute, MEDINET Co., Ltd., Tokyo, Japan; 3Surgery, Johns Hopkins University School of Medicine, Baltimore, MD
Background: Major histocompatibility complex class 1-related chain A/B (MIC A/B), expressed on the cell-surface of cancer cells, functions as a ligand for NKG2D, an important immunoreceptor expressed on gamma delta (γδ) T cells. We investigated the effect of gemcitabine (GEM), a key drug for pancreatic cancer treatment, on the expression of cell-surface MIC A/B in pancreatic cancer cells and resulting cytotoxity of γδ T cells.
Materials and Methods: We investigated the effect of GEM on the upregulation of cell-surface MICA/B expression by flow cytometry, utilizing seven pancreatic cancer cell lines. MICA and CD16 (γδ T and NK cells) expression from resected pancreatic cancer patient specimens, which received neoadjuvant chemotherapy (NAC) with GEM, was analyzed by immunohistochemistry.
Results: At a concentration not affecting cell growth, GEM increased the MICA/B expression effectively on all pancreatic cancer cell lines. Furthermore, GEM increased the MICA/B expression at a cytostatic concentration but did not increase the MICA/B expression at a cytotoxic concentration in the PANC-1 cell line (Fig.1A,B). Moreover, cytotoxic activity of γδT cells against PANC-1 was detected and function via NKG2D and MICA/B interaction. Immunohistochemical staining demonstrated that MICA expression in tumor cells (Fig.1C) and CD16 positive cells surrounding tumors (Fig.1D) were significantly higher in the NAC group compared to that of the control group. There was a significant correlation between NAC and MICA expression (p=0.002), as well as NAC and CD16 positive cell expression (p=0.001).
Conclusion: The present results indicate that low dose GEM-induced MICA/B expression activates innate immune function, rather than cytotoxicity in pancreatic cancer.
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