title: MHC class I chain-related molecule A and B expression is upregulated by cisplatin and associated with good prognosis in patients with non-small cell lung cancer.
abstract: MHC class I chain-related molecule A and B (MICA/B) are NK group 2 member D (NKG2D) ligands, which are broadly expressed in transformed cells. Both DNA damage-induced ataxia-telangiectasia-mutated (ATM)- and ATM and Rad3-related protein kinases (ATM-ATR) signaling and oncogene-induced PI3K-AKT signaling regulate the expression of NKG2D ligands, which promote NK cell-mediated cytotoxicity via NKG2D-NKG2D ligand interactions. NKG2D ligand overexpression was recently reported to be correlated with good prognosis in several types of cancer. However, the prognostic significance of NKG2D ligands in non-small cell lung cancer (NSCLC) remains unclear. Here, MICA/B expression was evaluated based on immunohistochemistry of 91 NSCLC samples from patients following radical surgery. In addition, expression of MICA/B was assessed in NSCLC cell lines treated with cisplatin in order to evaluate the regulatory mechanisms of MICA/B expression. Overall, 28 out of 91 (30.8%) specimens showed high expression level of MICA/B, which was associated with low (18)F-fluorodeoxyglucose uptake and manifestation of adenocarcinoma. After a median follow-up of 48.2 months, high MICA/B expression was associated with good recurrence-free survival (p = 0.037). In vitro assays using cell lines revealed that MICA/B expression was upregulated by cisplatin via ATM-ATR signaling, resulting in enhanced NK cell-mediated cytotoxicity. Upregulated MICA/B expressions in patients with radically resected NSCLC are predictive of good disease prognosis. Cisplatin-induced MICA/B upregulation is possibly an indirect mechanism by which the innate immune system eliminates tumor cells. NKG2D-NKG2D ligand-targeting therapy is a promising avenue for future immune-chemotherapy development.
authors.affiliation: Department of General Thoracic Surgery, Kawasaki Medical School, Matsushima 577, Kurashiki, 7010192, Japan. riki0716okita@yahoo.co.jp.
authors.forename: Riki
authors.initials: R
authors.lastname: Okita
authors.affiliation: Department of General Thoracic Surgery, Kawasaki Medical School, Matsushima 577, Kurashiki, 7010192, Japan.
authors.forename: Takuro
authors.initials: T
authors.lastname: Yukawa
authors.affiliation: Department of General Thoracic Surgery, Kawasaki Medical School, Matsushima 577, Kurashiki, 7010192, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Nojima
authors.affiliation: Department of General Thoracic Surgery, Kawasaki Medical School, Matsushima 577, Kurashiki, 7010192, Japan.
authors.forename: Ai
authors.initials: A
authors.lastname: Maeda
authors.affiliation: Department of General Thoracic Surgery, Kawasaki Medical School, Matsushima 577, Kurashiki, 7010192, Japan.
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Saisho
authors.affiliation: Department of General Thoracic Surgery, Kawasaki Medical School, Matsushima 577, Kurashiki, 7010192, Japan.
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Shimizu
authors.affiliation: Department of General Thoracic Surgery, Kawasaki Medical School, Matsushima 577, Kurashiki, 7010192, Japan.
authors.forename: Masao
authors.initials: M
authors.lastname: Nakata
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D002945:Cisplatin / Q000494:pharmacology*; D005260:Female; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis*; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D007694:Killer Cells, Natural / Q000187:drug effects / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; D015395:Histocompatibility Antigens Class I; C099187:MHC class I-related chain A; C098080:MICB antigen; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D002945:Cisplatin
keywords: Cisplatin; MICA/B (MHC class I chain-related molecule A and B); NK cell; Non-small cell lung cancer (NSCLC); Positron emission tomography (PET); Prognostic factor