Personalized therapy for non-small cell lung cancer (NSCLC), particularly lung adenocarcinoma, has recently been significantly improved by the discovery of various molecular targets. However, this has not been the case for lung squamous cell carcinoma (SCC). In the present study, we identified the family with sequence similarity 83, member B (FAM83B) as a candidate marker for SCC through a comprehensive gene expression analysis and examined its correlations with various clinicopathological factors. The subjects of this study consisted of 215 patients with NSCLC who underwent complete resection from 2005 to 2011 at the Fukushima Medical University Hospital (Fukushima, Japan). They included 102 patients with adenocarcinoma and 113 with SCC. FAM83B expression was first examined in some of the samples by gene expression analysis and western blotting, and then all clinical specimens were evaluated by immunohistochemistry (IHC). The relationship between the quantitative values for IHC and clinicopathological factors was statistically analyzed. The results showed that FAM83B mRNA expression was significantly higher in SCC than in normal lung or adenocarcinoma (P<0.0001). Immunoblot analysis also confirmed this trend. Specimens containing >10% positive area for FAM83B were judged as ‘positive’; 94.3% (107/113) of SCC and 14.7% (15/102) of adenocarcinoma were positive. Patients were divided into two subgroups according to expression (54 high-expression and 53 low-expression patients); the high-expression group was associated with a better disease-free survival (DFS) rate (P=0.042, log-rank test). In conclusion, FAM83B may be a reliable diagnostic and prognostic biomarker for SCC. Detailed analyses of FAM83B function in lung cancer are required to understand how its expression is associated with better prognosis in SCC.
BackgroundVaccine treatment using multiple peptides derived from multiple proteins is considered to be a promising option for cancer immune therapy, but scientific evidence supporting the therapeutic efficacy of multiple peptides is limited.MethodsWe conducted phase I trials using a mixture of multiple therapeutic peptide vaccines to evaluate their safety, immunogenicity and clinical response in patients with advanced/recurrent NSCLC. We administered two different combinations of four HLA-A24-restricted peptides. Two were peptides derived from vascular endothelial growth factor receptor 1 (VEGFR1) and 2 (VEGFR2), and the third was a peptide derived from up-regulated lung cancer 10 (URLC10, which is also called lymphocyte antigen 6 complex locus K [LY6K]). The fourth peptide used was derived from TTK protein kinase (TTK) or cell division associated 1 (CDCA1). Vaccines were administered weekly by subcutaneous injection into the axillary region of patients with montanide ISA-51 incomplete Freund’s adjuvant, until the disease was judged to have progressed or patients requested to be withdrawn from the trial. Immunological responses were primarily evaluated using an IFN-gamma ELiSPOT assay.ResultsVaccinations were well tolerated with no severe treatment-associated adverse events except for the reactions that occurred at the injection sites. Peptide-specific T cell responses against at least one peptide were observed in 13 of the 15 patients enrolled. Although no patient exhibited complete or partial responses, seven patients (47%) had stable disease for at least 2 months. The median overall survival time was 398 days, and the 1- and 2-year survival rates were 58.3% and 32.8%, respectively.ConclusionPeptide vaccine therapy using a mixture of four novel peptides was found to be safe, and is expected to induce strong specific T cell responses.Trial registrationThese studies were registered with ClinicalTrials.gov NCT00633724 and NCT00874588.
Abstract. Several types of immunosuppressive mechanisms in cancer patients have been reported to date. Regulatory T cells (Tregs), which express the master control transcription factor forkhead box P3 (FoxP3), are considered to play a major role in hampering antitumor immune response. However, the clinical significance of Tregs in patients with lung cancer has not been fully elucidated. The aim of this study was to investigate the clinical significance of Tregs in the peripheral blood and in resected cancer tissue specimens. We analyzed peripheral blood mononuclear cells (PBMCs) collected prior to surgery and resected specimens obtained from 67 patients with non-small-cell lung cancer (NSCLC). Peripheral Tregs (pTregs) were detected as CD4 + and FoxP3 + cells by flow cytometry. Immunohistochemical staining for CD4, CD8 and FoxP3 expression was also performed quantitatively by analyzing three randomly selected fields from central regions (cCD4, cCD8 and cFoxP3) and interstitial regions of the tumors (iCD4, iCD8 and iFoxP3). The associations between the expression frequencies in selected cells and clinicopathological parameters were statistically analyzed. The frequency of pTregs was found to be significantly higher in patients with pleural invasion (P=0.0049), vessel invasion (P=0.0009), lymphatic vessel invasion (P=0.0053) and recurrent disease (P=0.0112). Patients with T1 exhibited a significantly higher frequency of cCD4 (P=0.0199) and cCD8 (P=0.0058), although cFoxP3 expression was not significant (P= 0.0935). Patients with low levels of cFoxP3/iFoxP3 exhibited a significantly higher frequency of pTregs (P=0.0338) and patients with a high frequency of pTregs exhibited significantly poorer recurrence-free survival (P=0.0071). The multivariate analysis identified pTreg frequency as an independent prognostic factor (P=0.0458). Although the pathological analysis remains controversial, the frequency of pTregs in NSCLC patients may be a useful prognostic biomarker.
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