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

• DOI: 10.1007/s00262-016-1814-9
• Publication Date: 2016-03-03T11:41:22Z
• Authors: Riki Okita; Takuro Yukawa; Yuji Nojima; Ai Maeda; Shinsuke Saisho; Katsuhiko Shimizu; Masao Nakata
• Keywords: Adult; Aged, 80 and over; Male; Lung Neoplasms; Histocompatibility Antigens Class I; Antineoplastic Agents; Ataxia Telangiectasia Mutated Proteins; Kaplan-Meier Estimate; Middle Aged; Prognosis; Immunohistochemistry; 3. Good health; Killer Cells, Natural; 03 medical and health sciences; 0302 clinical medicine; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Humans; Female; RNA Interference; Cisplatin; Aged; Cell Proliferation

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.