The HLA class I antigen processing machinery (APM) plays a crucial role in the anticancer immune response. The aim of this study was to assess the clinical significance of APM components in esophageal cancer. A total of 11 esophageal cancer cell lines were evaluated by Western blot analysis for 13 HLA class I APM components. There was a different expression pattern among cancer cell lines for HLA class I heavy chain (HLA-HC), β2 microglobulin, Tapasin, TAP-1, TAP-2, LMP-7 and LMP-10. Immunohistochemical staining utilizing a tissue microarray method for HLA class I APM expression showing different expression patterns among cell lines was performed for 95 surgical specimens from patients with esophageal cancer. Prognostic factors were the down-regulation of HLA-HC, and the up-regulation of β2 microglobulin and TAP-1 in the cancer tissues. Multivariate analysis using a Cox regression model indicated that the down-regulation of HLA-HC, and up-regulation of TAP-1 in cancer tissues are independent, unfavorable prognostic factors (hazard ratio, 2.361 and 2.297; P=0.0141 and 0.0145, respectively). Although there was no significant difference in survival for selected p-stage I and II patients (n=54) in all APM components, only down-regulation of HLA-HC was an unfavorable prognostic factor by a Cox regression model for selected p-stage III and IV patients (n=41). In conclusion, the current results suggest that the down-regulation of HLA-HC in tumors is especially associated with a poor prognosis among advanced esophageal cancer patients.

A phase I+II clinical trial of vaccination with MAGE-A4 protein complexed with cholesteryl pullulan melanoma antigen gene-A4 nanogel (CHP-MAGE-A4) is currently underway in patients with MAGE-A4-expressing cancer. In the present study, the primary phase I endpoint was to test the safety of the administration of 300 µg CHP-MAGE-A4 with and without OK-432. Another aim of the study was to clarify the details of the specific humoral immune response to vaccination. The 9 patients enrolled for phase I were vaccinated 6 times, once every 2 weeks: 3 patients with 100 µg and 3 patients with 300 µg CHP-MAGE-A4, and 3 patients with 300 µg CHP-MAGE-A4 plus 0.5 clinical units of OK-432. Toxicities were assessed using Common Terminology Criteria for Adverse Events v3.0. Clinical response was evaluated by modified Response Evaluation Criteria in Solid Tumours. Immunological monitoring of anti-MAGE-A4-specific antibodies was performed by ELISA of pre- and post-vaccination patient sera. The 6 vaccinations produced no severe adverse events. Stable disease was assessed in 4/9 patients. Anti-MAGE-A4 total immunoglobulin (Ig)G titers increased in 7/9 patients. Efficacious anti-MAGE-A4 IgG1, 2 and 3 antibody responses were observed in 7/9 patients. Among them, positive conversions to T helper 2 (Th2)-type antibody responses (IgG4 and IgE) were observed after frequent vaccination in 4/7 patients. The Th2 conversion was possibly associated with undesirable clinical observations, including progressive disease and the appearance of a new relapse lesion. The present study suggested that frequent vaccinations activated a Th2-dominant status in the cancer patients. The identification of a time-dependent IgG subclass and IgE antibody production during vaccination protocols may be a useful surrogate marker indicating a potentially undesirable change of the immunological environment for an effective antitumor immune response in cancer patients.

Objective: IgG4-related sclerosing cholecystitis is generally associated with IgG4-related sclerosing cholangitis and presents with diffuse, circumferential thickening of the gallbladder wall. We report a rare case of localized IgG4-related sclerosing cholecystitis without IgG4-related sclerosing cholangitis, which was difficult to differentiate from gallbladder cancer preoperatively. Patient: A 56-year-old man with suspected IgG4-related disease or gallbladder cancer was admitted to our ward. The serum IgG4 level was elevated at 721 mg/dL. Computed tomography (CT) demonstrated focal wall thickening of the gallbladder fundus. Drip infusion cholecystocholangiography with CT revealed no dilation, stenosis, or border irregularity of the bile duct. Results: For diagnostic and treatment purposes, cholecystectomy with wedge resection of the gallbladder bed was performed. The pathological diagnosis was IgG4-related sclerosing cholecystitis. Conclusion: It is difficult to differentiate IgG4-related sclerosing cholecystitis from gallbladder cancer in cases involving localized thickening of the gallbladder wall. In similar cases, surgical resection with cancer in mind might be performed based on present clinical knowledge.

Melanoma antigen family A4 (MAGEA4), a cancer/testis antigen, is overexpressed and is thus an immunotherapy target in various malignant tumors, including non-small cell lung cancer. However, whether MAGEA4 induces or inhibits the apoptosis of lung cancer cells remains controversial, as is its prognostic significance, particularly since there is no reliable method with which to detect MAGEA4 specifically. In this study, we optimized assay conditions to detect MAGEA4 based on cells transiently transfected with MAGEA genes, and found that MAGEA4 was expressed in four of eight non-small cell lung cancer cell lines, and in 25.4% of clinical lung cancer specimens. We also found that MAGEA4 overexpression decreased apoptosis, as measured by the levels of cleaved caspase-3 in stably transfected 293F cells. Notably, patients with nuclear MAGEA4, but not p53 expression exhibited a significantly poorer survival than those expressing both nuclear MAGEA4 and p53. Indeed, multivariate analysis identified nuclear MAGEA4 as an independent prognostic factor (P=0.0042), albeit only in the absence of p53. In this study, to the best of our knowledge, we are the first to demonstrate that the function and prognostic value of MAGEA4 depends on its subcellular localization and on the p53 status.

No abstract