Expression Of Tumor-rejection Antigen Research Articles

Decitabine immunosensitizes human gliomas to NY-ESO-1 specific T lymphocyte targeting through the Fas/Fas Ligand pathway

BackgroundThe lack of effective treatments for gliomas makes them a significant health problem and highlights the need for the development of novel and innovative treatment approaches. Immunotherapy is an appealing strategy because of the potential ability for immune cells to traffic to and destroy infiltrating tumor cells. However, the absence of well-characterized, highly immunogenic tumor-rejection antigens (TRA) in gliomas has limited the implementation of targeted immune-based therapies.MethodsWe hypothesized that treatment with the demethylating agent, decitabine, would upregulate the expression of TRA on tumor cells, thereby facilitating enhanced surveillance by TRA-specific T cells.Results and DiscussionTreatment of human glioma cells with decitabine increased the expression of NY-ESO-1 and other well characterized cancer testes antigens. The upregulation of NY-ESO-1 made these tumors susceptible to NY-ESO-1-specific T-cell recognition and lysis. Interestingly, decitabine treatment of T98 glioma cells also sensitized them to Fas-dependent apoptosis with an agonistic antibody, while a Fas blocking antibody could largely prevent the enhanced functional recognition by NY-ESO-1 specific T cells. Thus, decitabine treatment transformed a non-immunogenic glioma cell into an immunogenic target that was efficiently recognized by NY-ESO-1--specific T cells.ConclusionsSuch data supports the hypothesis that agents which alter epigenetic cellular processes may "immunosensitize" tumor cells to tumor-specific T cell-mediated lysis.

Expression of tumor rejection antigens in colorectal carcinomas.

The authors recently reported that the SART2 and SART3 antigens encode tumor epitopes recognized by HLA-A24-restricted and tumor-specific cytotoxic T lymphocytes (CTLs) established from esophageal carcinoma patients. The current study investigated these antigens to explore a potential molecule for specific immunotherapy for colorectal carcinoma patients. The SART2 and SART3 antigens were investigated by Western blotting in colorectal carcinoma cell lines and in cancer tissues. For induction of CTLs, peripheral blood mononuclear cells (PBMCs) of HLA A-24-positive cancer patients were stimulated in vitro with peptides. The 140 kD SART3 antigen was expressed in both the cytosol and nuclear fractions of all six colon carcinoma cell lines, 27 of 41 (65.9%) cytosol fractions, 30 of 41 (73.2%) nuclear fractions of colorectal carcinoma tissue samples, and in 0 of 7 non-tumorous tissues. The 100 kD SART2 antigen was expressed in the cytosol fractions of 2 of 6 colon carcinoma cell lines, 5 of 20 (25%) cytosol fractions of colorectal carcinoma tissue samples, and in 0 of 7 non tumorous tissues. HLA-A24-restricted CTLs cytotoxic to colon carcinoma cells were induced from PBMCs of colon carcinoma patients by stimulation with the two immunogenic peptides of SART3. The SART3 antigen could be an appropriate target molecule for specific immunotherapy for colorectal carcinoma patients.

Expression of tumor-rejection antigens in gynecologic cancers.

We recently reported the four tumor‐rejection antigens (SART1259 SART2, SART3, and ART4) that possess tumor epitopes capable of inducing HLA‐A2402‐restricted cytotoxic T lymphocytes (CTLs) in cancer patients. This study investigated the expression of these tumor antigens in gynecologic cancers, including 33 ovarian cancers, 38 cervical cancers, and 40 endometrial cancers. SART1259 antigen was detected in 56%, 35%, and 30% of ovarian, cervical and endometrial cancers, while SART2 antigen was detected in 46%, 66%, and 30% of these cancers, respectively. Both SART3 and ART4 antigens were detectable in the majority of these gynecologic cancers tested. In contrast, none of these antigens was detectable in any of the normal ovarian and uterine tissues tested. Peripheral blood mononuclear cells (PBMCs) of HLA‐A24+ patients with gynecologic cancers were found to produce significant levels of interferon‐γ in response to HLA‐A24+ SART3+ gynecologic cancer cells after having been stimulated three times in vitro with either SART3109–118 or SART3315–323 peptide. These PBMCs lysed HLA‐A24+ SART3+ gynecologic cancer cells, but not HLA‐A24‐ SART3+ gynecologic cancer cells or HLA‐A24+ normal cells. Therefore, these four antigens and their peptides, including SART3 peptides, would be appropriate molecules for use in specific immunotherapy of HLA‐A24+ gynecologic cancer patients.

The expression of tumor-rejection antigen “Mage” genes in pancreatic carcinoma

The expression of tumor-rejection antigen “Mage” genes in pancreatic carcinoma

The expression of tumor-rejection antigen “MAGE” genes in human gastric carcinoma

Background & Aims The genes MAGE-1 and MAGE-3 both encode melanoma peptide antigens recognized by major histocompatibility complex-restricted cytotoxic T lymphocytes. The antigens may be a target for immunotherapy. There is, however, little information on the expression of these genes in gastric carcinomas. Therefore, the expression of MAGE genes in gastric carcinomas was evaluated. Methods The expression of MAGE-1, MAGE-2, and MAGE-3 genes in tumors and corresponding normal tissue specimens was studied using a reverse-transcription polymerase chain reaction. The results were analyzed according to clinicopathologic factors of the tumor. Results In the 68 gastric carcinomas studied, MAGE-1, MAGE-2, and MAGE-3 messenger RNA were detected in 41%, 31%, and 38%, respectively. Fifty percent of the gastric carcinomas expressed at least one of the MAGE genes. Messenger RNA for the three MAGE proteins was not detected in normal gastric tissue. MAGE gene expression in gastric carcinomas was not associated with a significant clincopathology of the tumor. However, gene expression was lower in mucinous carcinomas (3 of 10). Conclusions MAGE-1, MAGE-2, and MAGE-3 are expressed in a high percentage of gastric carcinomas. These tumor rejection antigens may provide tumor-specific targets for immunotherapy.

Rat Adenocarcinoma 13762 Expresses Tumor Rejection Antigens but Tumor-Bearing Animals Exhibit Tumor-Specific Immunesuppression

Rat adenocarcinoma 13762 was adapted to continuous growth in culture and used in a variety of experiments to investigate the immune response to inoculation of animals with replication-defective tumor cells. The results demonstrate that 13762 cells express tumor-specific tumor rejection antigens that elicit protective immunity to tumorigenic challenge. By several criteria there is no apparent humoral component of the anti-tumor immunity; however, antitumor immunity is characterized by nylon-wool nonadherent spleen T cells. Anti-tumor T cells demonstrate tumoricidal activity in local adoptive transfer assays and are not found in spleens of naive animals or animals immunized against either nontumorigenic Rat 1 cells or a syngeneic fibrosarcoma. Despite the expression of tumor rejection antigens 13762 tumor, and the demonstrable ability of injection of irradiated tumor to induce anti-tumor immunity, tumors elicited in unimmunized syngeneic animals grow progressively. The reasons for growth of antigenic tumor are unknown but are shown not to be due to defective antigen expression in 13762 tumor since, in addition to being able to elicit T cell immune response in immunized animals, 13762 tumor expresses MHC Class I molecules and can be a target for allogeneic T cell recognition in vitro. These data suggest that in tumor-bearing animals an effective anti-tumor immune response is either not initiated or down-regulated. Since animals bearing 13762 tumors can be immunized against an unrelated syngeneic sarcoma, can produce humoral responses to several protein antigens, and can produce delayed type hypersensitivity response against dinitrofluorobenzene, the immune response to 13762-induced tumors appears specifically suppressed. In support of this contention, 13762 cells express

The expression of tumor rejection antigen on rat fetus fibroblasts transformed by the ras oncogene.

The expression of tumor rejection antigens (TRA) was analyzed on clones of rat fetus‐derived fibroblasts, WFB, transformed or transfected by oncogenes. It was shown that a tumorigenic W14 clone, which is an activated H‐ras transformant of parental WFB, expressed TRA in transplantation experiments using syngeneic WKA rats. The data also showed that W14 TRA was acquired in the event of cell transformation, since it was not detected on parental non‐transformed WFB cells or Wmyc‐4 clone which is a transfectant of WFB by mouse plasmacytoma‐derived c‐myc DNA. However, TRA was not expressed or at least was not detected on highly tumorigenic W31, another clone of H‐ras transformants of parental WFB, in the transplantation experiments. We also assessed the level of expression of major histocompatibility antigens (MHC) class I molecules on these cells by using R4‐8B1 Mab that reacts specifically with rat class I antigen. The data indicated that it was decreased on W14, W31, and Wmyc‐4, but not on parental WFB. Although this molecule was weakly positive on W14 cells, W31 and Wmyc‐4 showed even greater decreases. These data may indicate that the TRA expression and its recognition by syngeneic hosts are dependent upon the transformed clones, although their parental cell is the same. We discuss in detail this difference of expression and recognition of TRA in the context of the cell transforming process.