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The purpose of the present study was to identify a novel tumorspecific antigen capable of inducing a specific cellular immune response in lung cancer patients. The co-culture of regional lymph node lymphocytes and the CD80-transfected autologous lung adenocarcinoma cell line H1224L resulted in a successful induction of bulk cytotoxic T lymphocytes (CTL). CTL clone L7 ⁄ 8 was established by the limiting dilution method from these bulk CTLs and lysed H1224L but not autologous Epstein-Barr virus-transformed B cells or K562. The CTL clone also recognized allogeneic lung cancer cell lines in an HLA-A*31012-restricted manner. Using the CTL clone, an antigen-coding gene was identified using the cDNA expression cloning technique, which encodes ribosomal protein L19 (RPL19). Finally, a 9 mer antigenic peptide was identified by means of construction of mini-genes. RPL19 was overexpressed in the lung cancer tissue from patient H1224. All of the normal tissues examined expressed lower levels of RPL19 mRNA than that of the lung cancer tissue. RPL19 was also found to be overexpressed in 12 of 30 (40% %) non-small-cell lung cancer tissues by immunohistochemical staining. The expression level of RPL19 in tumor cell lines correlated positively with the production of interferon (IFN)-c by CTL clone L7 ⁄ 8 in response to such cell lines. In addition, the suppression of RPL19 expression by transfection with small interfering RNA resulted in the suppression of cyclinD1, D3 synthesis, and the growth inhibition of lung cancer cell lines overexpressing RPL19. Therefore, this growth suppression could be ascribed to the inhibition of the cell cycle. These results may indicate that RPL19 is a novel overexpressed antigen which may therefore be a useful candidate as a target for specific immunotherapy. (Cancer Sci 2010; 101: 46-53) L ung cancer is one of the most common malignant tumors in the world and has the highest age-adjusted death rate among malignancies in 45 countries.(1,2) The most effective therapy is a surgical resection in early stage non-small-cell lung cancer (NSCLC), because advanced NSCLC tends to show a poor response to radiotherapy and chemotherapy. It is important to concentrate our efforts on developing more effective cancer therapies.Specific immunotherapies have been utilized since the identification of the tumor-specific antigen derived from malignant melanoma.(3) Tumor-associated antigens are classified into cancer-testis antigen, overexpressed antigen, mutated antigen, and differentiation antigen, which have been identified with CTL clones derived from regional lymph node lymphocytes (RLNL), peripheral blood lymphocytes (PBL), and tumor-infiltrating lymphocytes (TIL).(3-6) These antigens have been employed for cancer vaccines. (7)(8)(9) In 2004, however, the results of clinical vaccine studies in patients with metastatic cancer were reviewed and the clinical response was not satisfactory.(10) The identification of a novel tumor antigen for more effective immunotherapy to induce clinical response is further need...

Abstract. It is not easy to induce cytotoxic T lymphocytes (CTLs) against cancer in in vitro culture. Regulatory T cells (Tregs) are considered to play a pivotal role in tumor immune escape. In this study, we analyzed the distribution of Tregs among tumor-infiltrating lymphocytes (TILs), regional lymph node lymphocytes (RLNLs) and peripheral blood lymphocytes (PBLs) in patients with lung cancer, and analyzed the effect of Tregs on the induction of CTLs in vitro.

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HLA class I loss in NSCLC was related to smoking history and MAGE-A4 expression of tumors. HLA class I loss in smokers or patients with the MAGE-A4 gene was a prognostic factors in NSCLC.

Extraskeletal osteosarcoma is a rare malignant tumor occurring very rarely in the pleura. We herein report the case of 67-year-old man with asbestos exposure, who underwent biopsies of the large tumor from the chest wall, and diagnosed as a suspicious of fibrosarcoma. Surgical resection was done, and the pathological diagnosis was extraskeletal osteosarcoma arising from the pleura. The differential diagnosis is malignant pleural mesothelioma with osseous and cartilaginous which is also very rare and one of the histopathological subtypes with heterologous elements. Identification of epithelial components, labeling for cytokeratins in spindle cells and its' anatomical distribution may help to distinguish them. In the neoplasm arising from the parietal pleura, primary extraskeletal osteosarcoma of the pleura is very rare, but should be considered.Keywords: extraskeletal osteosarcoma, pleura, asbestos exposure Introduction Extraskeletal osteosarcoma is rare, accounting for 1%-2% of all soft tissue sarcomas and 4% of all osteosarcomas, 1� and extraskeletal osteosarcoma arising from the pleura is very rare. There have been only 8 reported cases of primary extraskeletal osteosarcoma of the pleura, including our case. In our case, it is difficult to distinguish malignant pleural mesothelioma with osseous and cartilaginous. We herein report a case of extraskeletal osteosarcoma of the pleura with occupational asbestos exposure, diagnosed by thoracoscopic biopsies, and treated by surgical resection and systemic chemotherapy after the operation. Case ReportA 67-year-old man presented to another hospital in October 2008 for a comprehensive medical examination. Calcification was discovered in a portion of the right parietal pleura by chest CT. Since the patient had a history of asbestos exposure, it was followed up as calcified pleural plaques. In March 2009, the patient developed dyspnea on exertion and cough, and presented again to the same hospital. His chest radiography showed a massive right pleural effusion. In April 2009, the patient was referred to our hospital with a suspicion of malignant pleural mesothelioma.His past medical history included cholelithiasis at age 45 yrs, and type 2 diabetes and hyperlipidemia at age 60 yrs. He had smoked 15 cigarettes a day for 46 yrs. His family history was non-contributory. He worked in the construction of electric power substations from age 28-60 and had a history of asbestos exposure. His present status was unremarkable except for the chest region with diminished breath sounds over the right middle and lower lung fields. The blood biochemistry test results on admission were normal except for a slightly high CRP at 1.1 mg/dL. Tumor markers CEA, CYFRA, Pro-GRP, and NSE were within their normal ranges. Extraskeletal osteosarcoma is a rare malignant tumor occurring very rarely in the pleura. We herein report the case of 67-year-old man with asbestos exposure, who underwent biopsies of the large tumor from the chest wall, and diagnosed as a suspicious of fibrosarcoma. Surgical res...

The present study analyzed the antitumor effect of γδT cells transduced with the TCR of cancer‐specific CTLs to establish forceful cancer‐specific adoptive immunotherapy. We cloned the TCRαβ genes from CTLs showing HLA‐B15 restricted recognition of Kita‐Kyushu lung cancer antigen‐1 (KK‐LC‐1), a cancer/germline gene antigen, identified in a lung adenocarcinoma case (F1121). The TCRαβ and CD8 genes were transduced into γδT cells induced from PBLs of healthy volunteers stimulated with zoledronate and IL‐2. The KK‐LC‐1‐specific TCRαβ‐CD8 γδT cells showed cytotoxic activity against the KK‐LC‐1 positive lung cancer cell line F1121L and produced IFN‐γ against F1121L and KK‐LC‐1 peptide‐pulsed F1121 EBV‐B cells. These responses were blocked by HLA class I and HLA‐B/C antibodies. An in vivo assay using NOD/SCID mice with xenotransplantation of human lung cancer cells was performed, and the TCRαβ‐CD8 transduced γδT cells (TCRαβ‐CD8 γδT cells) were intravenously injected. Growth inhibition of KK‐LC‐1+, HLA‐B15+ lung cancer cells was confirmed in mice with injection of the TCRαβ‐CD8 γδT cells from 1 wk after xenotransplantation of cancer cells but not in those treated 2 wk after xenotransplantation. The resected specimens of the tumor, 2 wk after xenotransplantation, highly expressed FasL but not programmed death ligand‐1 (PD‐L1) by immunohistochemical staining. FasL highly expressed cancer cells xenotransplanted 2 wk ago were resistant to TCRαβ‐CD8 γδT cells injection. These results suggested that apoptosis of Fas‐positive TCRαβ‐CD8 γδT cells may be induced by a Fas‐mediated signal after interacting with FasL‐positive cancer cells.

Injection of antigen into the anterior chamber of the eye induces suppression of antigen-specific DTH, called anterior chamber-associated immune deviation (ACAID). It has been shown that the spleen is required for the induction of ACAID and detecting the ACAID-inducing signal from the eye. To examine the in vivo role of spleen cells, fractions of spleen cells were adoptively transferred into splenectomized mice. The present study showed that DTH was not suppressed in splenectomized mice, but was inhibited in splenectomized mice transferred with a primed CD4+ T cell-containing fraction of spleen cells. This indicates that the splenic CD4+ T cells comprise the regulatory T cells for the DTH response. When we examined the cytokine profile of the infiltrating T cells in the eye of primed mice by reverse transcriptase-polymerase chain reaction (RT-PCR), we found that they expressed IL-4, IL-10 mRNA (Th2 type), but not IL-2 and interferon-gamma (IFN-gamma) mRNA (Th1 type). By contrast, T cells which can elicit normal DTH response expressed IL-2 and IFN-gamma mRNA. These results suggest that splenic CD4+ T cells comprising the regulatory phenotype are required for the induction of ACAID, and that a DTH response to the antigen may be prevented by Th2-dominant CD4+ T cells.