Overexpression of NK cell-activating ligand MICA/B correlates with superior outcomes and might be a therapeutic target for chemo-immunotherapy in non-small-cell lung cancer

Aim/Background

MICA and MICB (MICA/B) are the NK group 2 member D (NKG2D) ligands that are broadly expressed in transformed cells and promote natural killer (NK) cell-mediated cytotoxicity via NKG2D–NKG2D ligand interaction. NKG2D ligand overexpression has been recently reported to correlate with good prognosis in different types of cancer, however, the prognostic significance of MICA/B expression in NSCLC tissue has never been reported.

Methods

MICA/B expression was evaluated by immunohistochemistry in 91 consecutive NSCLC patients after radical surgery; the clinicopathological features as well as clinical outcome were also analyzed. Additionally, MICA/B expressions as well as NK cell-mediated cytotoxicity in NSCLC cell line A549 treated with chemotherapeutic regents were assessed by flowcytoetric analysis and LDH release assay, respectively.

Results

Overall, 28 of 91 (30.8%) specimens overexpressed MICA/B. The MICA/B overexpression was associated with low F18-fluorodeoxyglucose (FDG) uptake and adenocarcinoma histology. After a median follow-up of 48.2 months, MICA/B overexpression was associated with good recurrence-free survival (RFS) (p = 0.037). In multivariate analysis, MICA/B overexpression emerged as an independent prognostic factor for RFS (p = 0.046). In vitro assay, chemotherapeutic reagents upregulated MICA/B expression via ATM-ATR pathway, resulted in enhanced NK cell-mediated cytotoxicity in A549 cells.

Conclusions

MICA/B overexpression in patients with radically resected NSCLC is predictive of good prognosis, and chemotherapeutic regent enhances NK cell-mediated cytotoxicity via upregulation of MICA/B.

Clinical trial identification

Disclosure

M. Nakata: research fundings from Kyowa-Kirin, Eli Lilly Japan and CSL Behring. All other authors have declared no conflicts of interest.