title: Low-dose gemcitabine induces major histocompatibility complex class I-related chain A/B expression and enhances an antitumor innate immune response in pancreatic cancer.
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.
authors.affiliation: Department of Gastroenterological Surgery, Kanazawa University Hospital, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8641, Japan. tomoharumiya@gmail.com.
authors.forename: Tomoharu
authors.initials: T
authors.lastname: Miyashita
authors.affiliation: Medinet Medical Institute, MEDINET Co., Ltd., 2-2-8 Tamagawadai, Setagaya-ku, Tokyo, 158-0096, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Miki
authors.affiliation: Medinet Medical Institute, MEDINET Co., Ltd., 2-2-8 Tamagawadai, Setagaya-ku, Tokyo, 158-0096, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kamigaki
authors.affiliation: Department of Gastroenterological Surgery, Kanazawa University Hospital, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8641, Japan.
authors.forename: Isamu
authors.initials: I
authors.lastname: Makino
authors.affiliation: Department of Gastroenterological Surgery, Kanazawa University Hospital, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8641, Japan.
authors.forename: Hisatoshi
authors.initials: H
authors.lastname: Nakagawara
authors.affiliation: Department of Gastroenterological Surgery, Kanazawa University Hospital, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8641, Japan.
authors.forename: Hidehiro
authors.initials: H
authors.lastname: Tajima
authors.affiliation: Department of Gastroenterological Surgery, Kanazawa University Hospital, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8641, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Takamura
authors.affiliation: Department of Gastroenterological Surgery, Kanazawa University Hospital, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8641, Japan.
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Kitagawa
authors.affiliation: Department of Gastroenterological Surgery, Kanazawa University Hospital, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8641, Japan.
authors.forename: Sachio
authors.initials: S
authors.lastname: Fushida
authors.affiliation: Department of Surgery, Johns Hopkins University School of Medicine, 4940 Eastern Avenue, Baltimore, MD, 21224, USA.
authors.forename: Ali K
authors.initials: AK
authors.lastname: Ahmed
authors.affiliation: Department of Surgery, Johns Hopkins University School of Medicine, 4940 Eastern Avenue, Baltimore, MD, 21224, USA.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Duncan
authors.affiliation: Department of Surgery, Johns Hopkins University School of Medicine, 4940 Eastern Avenue, Baltimore, MD, 21224, USA.
authors.forename: John W
authors.initials: JW
authors.lastname: Harmon
authors.affiliation: Department of Gastroenterological Surgery, Kanazawa University Hospital, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8641, Japan.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Ohta
mesh_terms: D000368:Aged; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004334:Drug Administration Schedule; D005260:Female; D058851:GPI-Linked Proteins / Q000235:genetics / Q000276:immunology; D015972:Gene Expression Regulation, Neoplastic; D015395:Histocompatibility Antigens Class I / Q000235:genetics* / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects*; D008297:Male; D008875:Middle Aged; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000235:genetics / Q000276:immunology; D020360:Neoadjuvant Therapy / Q000379:methods; D010179:Pancreas / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000235:genetics / Q000276:immunology; D017452:Receptors, IgG / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D000093542:Gemcitabine
chemical_list: C428200:FCGR3B protein, human; D058851:GPI-Linked Proteins; D015395:Histocompatibility Antigens Class I; C527085:KLRK1 protein, human; C099187:MHC class I-related chain A; C098080:MICB antigen; D055655:NK Cell Lectin-Like Receptor Subfamily K; D016692:Receptors, Antigen, T-Cell, gamma-delta; D017452:Receptors, IgG; D003841:Deoxycytidine; D000093542:Gemcitabine
keywords: Chemotherapy; Low-dose gemcitabine; Major histocompatibility complex class 1-related chain A/B; Pancreatic cancer; γδ T cell