Diagnostic and prognostic impact of serum‐soluble UL16‐binding protein 2 in lung cancer patients

Abstract

UL16-binding protein 2 (ULBP2) is one of the ligands for NKG2D (NKG2DL). ULBP2 expression is induced in transformed cells and is recognized by immune effector cells via the activating NKG2D immunoreceptor. Soluble forms of NKG2DL have been reported in the serum of patients with several types of cancer. The present study investigated the diagnostic and prognostic significance of serum-soluble ULBP2 (sULBP2) in lung cancer patients. We used flow cytometry to evaluate the surface expression of NKG2DL by various lung cancer cells, while sULBP2 was measured using our original ELISA. In addition, the immunological effect of sULBP2 on peripheral blood mononuclear cells (PBMC) was examined by the 51 Cr release assay. We found that ULBP2 was highly expressed and that the sULBP2 level was elevated in supernatants of cultured non-small-cell lung cancer (NSCLC) cells as well as in the serum of NSCLC patients. ULBP2 levels were especially high in squamous cell carcinoma (SQ) patients. Clinical stage IIIB and IV NSCLC patients with a sULBP2 level ! 8.7 pg/mL showed significantly shorter survival than patients with sULBP2 <8.7 pg/mL. In multivariate analysis, a sULBP2 level ! 8.7 pg/mL (hazard ratio [HR], 2.13; P = 0.038) and clinical stage IV (HR, 2.65; P = 0.019) were independent determinants of a poor outcome. As a possible mechanism, we demonstrated that sULBP2 directly suppresses the cytolytic activity of PBMC. In conclusion, ULBP2 is the most significant NKG2DL for lung cancer, and sULBP2 is useful in the diagnosis of SQ and as a prognostic indicator for patients with advanced NSCLC. (Cancer Sci 2012; 103: 1405-1413

Expression and prognostic significance of unique ULBPs in pancreatic cancer

“…Similarly, Cho et al showed that m-ULBP1–5 were all expressed in cervical cancer tissue and that m-ULBP1 was an independent predictor of good prognosis regarding both DFS and OS 19. Yamaguchi et al demonstrated that s-ULBP2 was useful in the diagnosis of squamous cell carcinoma and could be considered a prognostic indicator for patients with advanced non-small-cell lung cancer 38. However, not all experiments were consistent with our results 21,39.…”

Secretory pathways generating immunosuppressive NKG2D ligands: New targets for therapeutic intervention

“…The presence of sMICA in Stage III and IV PDAC patient sera and the accompanying downregulation of NKG2D receptor on NK cells revealed both parameters to be independent markers of pancreatic malignant disease progression 32 . Similarly, elevated sMICB or sULBP2 levels in sera have also been associated with worse outcome, including sMICB in late-stage oral squamous cell carcinoma (OSCC) 38 and melanoma patients, 39 and sULBP2 among melanoma 35 and NSCL patients 37 …”

“…Unlike MICA, little is known about the presence of other ligands in solid cancers. High levels of soluble MICB (sMICB) have been observed in PDAC patient sera 33 and in the culture media supernatant of human cervical cancer cell lines, 36 whereas elevated soluble ULBP2 (sULBP2) has been detected in melanoma 35 and non-small cell lung cancer (NSCL) patients 37 …”

NKG2D and its ligands in cancer

“…Shedding of other family of NKG2D ligands, such as ULBP2 has also been reported to correlate with poor prognosis in selected cancer of solid tumors and hematological malignancies [48–52]. Most recent clinical studies in cohorts of melanoma patients suggested that baseline serum soluble NKG2D ligands may negatively impact clinical outcome of immune checkpoint blockade therapy [10 ● ].…”