Studies of the administration of interleukin-2 to patients with metastatic melanoma or kidney cancer have shown that immunological manipulations can mediate the durable regression of metastatic cancer. The molecular identification of cancer antigens has opened new possibilities for the development of effective immunotherapies for patients with cancer. Clinical studies using immunization with peptides derived from cancer antigens have shown that high levels of lymphocytes with anti-tumour activity can be raised in cancer-bearing patients. Highly avid anti-tumour lymphocytes can be isolated from immunized patients and grown in vitro for use in cell-transfer therapies. Current studies are aimed at understanding the mechanisms that enable the cancer to escape from immune attack.

Progress in human tumour immunology and immunotherapy

Publisher Summary It is known for some time that malignant transformation of human cells may be associated with the appearance of tumor associated antigens (TAA). Decades of research have been aimed at the identification of TAA that can serve as targets for the immunotherapy of malignant diseases. The dramatic progress in the understanding of molecular basis of target cell recognition by cytotoxic T lymphocytes (CTL) has provided the background to design effective strategies to identify TAA recognized by CTL on tumor cells. The extensive application of these strategies by a number of investigators has resulted in the identification of various families of TAA on various types of solid tumors. Mouse tumor models have played an important role in elucidating the mechanisms by which the immune system interacts with tumor cells and eradicates cancer. The second line of evidence is represented by the phenomenon of a “mixed response.” A mixed response occurs rather frequently in patients with metastases, although its actual frequency is not documented. Mixed responses are characterized by the different behavior of synchronous metastases in response to T cell-based immunotherapy. This important finding suggests that TAA-specific CTL may be present in some cancer patients but are unable to attack tumor cells due to the presence of inhibitory receptors.

Escape of human solid tumors from T-cell recognition: molecular mechanisms and functional significance.

The last seven years have been exciting in the world of mucin biology. Molecular analyses of mucin genes and deduced protein structures have provided insight into structural features of mucins and tools with which to examine expression, secretion, and glycosylation, thereby enabling a better understanding of the role of mucins in normal physiological processes and in disease. Functional studies are in progress both in vitro using cDNAs and cell lines and in vivo utilizing mutant mice in which a particular mucin gene has been inactivated or overexpressed. These studies should help determine whether the functions of mucins are restricted to protection and lubrication, or if they are involved in the adhesion of tumor cells to other cells or tissue components or in modulation of the immune system.

Epithelial Mucin Genes

Complete list of abbreviations of tumor antigens 707-AP 707 alanine proline-AFP alpha (α)-fetoprotein-ART-4 adenocarcinoma antigen recognized by T cells 4 BAGE B antigen-β-catenin/m β-catenin/mutated-Bcr-abl breakpoint cluster region-Abelson - CAMEL CTL-recognized antigen on melanoma CAP-1 carcinoembryonic antigen peptide-1-CASP-8 caspase-8 CDC27m cell-division-cycle 27 mutated-CDK4/m cycline-dependent kinase 4 mutated-CEA carcino-embryonic antigen-CT cancer/testis (antigen)-Cyp-B cyclophilin B DAM differentiation antigen melanoma (the epitopes of DAM-6 and DAM-10 are equivalent, but the gene sequences are different; DAM-6 is also called MAGE-B2. and DAM-10 is also called MAGE-B1) ELF2M elongation factor 2 mutated ETV6-AML1 Ets variant gene 6/acute myeloid leukemia 1 gene ETS G250 glycoprotein 250 - GAGE G antigen GnT-V N-acetylglucosaminyltransferase V -Gp100 glycoprotein 100 kDa-HAGE helicose antigen-HER-2/neu human epidermal receptor-2/ neurological - HLA-A * 0201-R1701 arginine (R) to isoleucine (I) exchange at residue 170 of the α-helix of the α2-domain in the HLA-A2 gene HPV-E7 human papilloma virus E7 HSP70-2M heat shock protein 70-2 mutated HST-2 human signet ring tumor-2 hTERT or hTRT human telomerase reverse transcriptase-iCE intestinal carboxyl esterase KIAA0205 name of the gene as it appears in databases-LAGE L antigen LDLR/FUT low-density lipid receptor/GDP-L-fucose: β-D-galactosidase 2-α-L-fucosyltransferase MAGE melanoma antigen MART-1/Melan-A melanoma antigen recognized by T cells-1/melanoma antigen A MC1R melanocortin 1 receptor Myosin/m myosin mutated-MUC1 mucin 1-MUM-1, -2, -3 melanoma ubiquitous mutated 1, 2, 3 NA88-A NA cDNA clone of patient M88-NY-ESO-1 New York-esophagus 1 - P15 protein 15 p190 minor bcr-abl protein of 190 kDa ber-abl Pml/RARα promyelocytic leukaemia/retinoic acid receptor α-PRAME preferentially expressed antigen of melanoma PSA prostate-specific antigen-PSM prostate-specific membrane antigen-RAGE renal antigen RU1 or RU2 renal ubiquitous 1 or 2 SAGE sarcoma antigen SART-1 or SART-3 squamous antigen rejecting tumor 1 or 3-TEL/ AML1 translocation Ets-family leukemia/acute myeloid leukemia 1 TPI/m triosephosphate isomerase mutated TRP-1 tyrosinase related protein 1, or gp75 TRP-2 tyrosinase related protein 2 TRP-2/ INT2 TRP-2/intron 2 WT1 Wilms' tumor gene Abbreviations used ALL acute lymphoblastic leukemia AML acute myeloid leukemia-APL acute promyelocytic leukemia-CML chronic myelogenous leuke mia-CTL cytotoxic T lymphocytes-Ets E-26 transforming specific (family of transcription factors) H/N head and neck-MHC major histocompatibility complex-NSCLC non-small cell lung carcinoma-ORF open reading frame RCC renal cell carcinoma-SCC squamous cell carcinoma-TSTA tumor-specific transplantation antigens.

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A listing of human tumor antigens recognized by T cells.

W e have come a long way since the identification of the first human tumor antigen recognized by autologous CTL. This report provides a brief appraisal of these antigens and their potential for cancer immunotherapy. Our comments will be restricted to nonviral antigens. The initial work carried out on mouse tumors revealed two possible mechanisms for generating new antigens that might be suflficiendy tumor-specific to be of relevance to immunotherapy. The first mechanism involved a point mutation, and the second involved the transcriptional activation o fa gene not expressed in normal tissues (1-3). Subsequent work on mouse tumors provided two interesting examples of tumor antigens resulting from point mutations (4, 5). Tumor-specific Shared Antigens. Three families of genes that appear to code for highly specific tumor antigens have been identified so far, namely, the MAGE, BAGE, and GAGE genes (6-9). These genes are frequently expressed in a wide range of tumor types such as melanoma, lung carcinoma, sarcoma, and bladder carcinoma, but very rarely in other tumor types such as brain tumors, renal carcinoma, and leukemia (7, 10-12). The only normal tissues where expression of these genes has been observed are testis and placenta (7). Starting from CTL clones obtained by stimulating lymphocytes with an autologous melanoma cell line, six antigens encoded by MAGE-1, MAGE-3, BAGE, and GAGE have been identified (8, 9, 13-15). For these six antigens, both the presenting HLA molecule and the antigenic peptide have been completely defined. Remarkably, all the relevant CTL were derived from the same melanoma patient, a patient with metastatic disease who enjoyed an extraordinarily favorable chnical course. Blood samples from several patients with a tumor expressing some or all of these genes were tested, and no such CTL were obtained by stimulating the lymphocytes with autologous tumor cells. More than 60% of Caucasian melanoma patients bear one of the presently defined antigens encoded by MAGE, BAGE, and GAGE. For other cancers such as head and neck tumors and bladder cancer, the frequencies range from 40% to 28%. For several reasons, it appears increasingly unlikely that immunization of patients against one of these antigens will cause harmful immunological side effects caused by the expression of the relevant gene in the testis. First, this expression appears to occur in germline cells, more precisely spermatocytes and spermatogonia (16). A similar observation has been made with the mouse equivalent of a MAGE gene by in situ hybridization (17). Because these germline cells do not express classical M H C class I molecules, gene expression should not result in antigen expression (18). These conclusions are further strengthened by immunization studies carried out with mouse tumor antigen P815A, which is encoded by a gene that is also expressed only in the testis. After immunization with P815 tumor cells, which carry this antigen, male mice produced a strong CTL response. No inflammation of the testis was observed in the following months, and the fertihty of these mice was normal (Uyttenhove, C., manuscript in preparation). A new mode of origin for antigens that are also tumorspecific shared antigens is described in this issue (19). Here, it seems that a gene that is ubiquitously expressed, namely, N-acetyl-glucosaminyltransferase V, contains an intron that appears to carry near its end a promoter that is activated only in melanoma cells. This atypical activation occurs in >50% of melanomas. This produces a message containing a new open reading frame, which codes for the antigenic peptide in its intronic part. Some CTL directed against breast, ovarian, and pancreatic carcinomas recognize an epitope of mucin, a surface protein composed of multiple tandem repeats of 20 amino acids (20-23). Whereas in normal cells mucin is heavily glycosylated, in these tumors the peptide repeats are unmasked by underglycosylation, resulting in CTL recognition. Remarkably, this recognition, which depends on the presence of multiple repeats, occurs in the absence of HLA restriction. The presence of this epitope was recently reported on myeloma cells, and mucin-specific CTL were isolated from the blood of a myeloma patient (24). These mucin antigens appear to be very specific for tumor cells, and the lack of HLA restriction should facilitate therapeutic vaccination trials. Differentiation Antigens. The observation that autolognus CTL can be generated readily against differentiation antigens present on normal melanocytes as well as melanoma cells was unexpected. Four genes encoding melanoma differentiation antigens have been identified: tyrosinase, Melan-A/Mart-1, gpl00, and gp75 (25-30). Most of the identified antigenic peptides are presented by HLA-A2, but other HLA-peptide combinations have been found (29-38). One tyrosinase peptide is presented by HLA-DR4 to CD4 T cells (34). The pattern of CTL precursors directed against these dif-

https://rupress.org/jem/article-pdf/183/3/725/1107908/725.pdf

Human tumor antigens recognized by t lymphocytes

Synthetic peptide analogues of sequences in the HER-2 protooncogene (HER-2) were selected based on the presence of HLA-A2.1 anchor motifs to identify the epitopes on HER-2 recognized by ovarian tumor-reactive CTL. 19 synthetic peptides were evaluated for recognition by four HLA-A2 ovarian-specific cytotoxic T lymphocyte (CTL) lines obtained from leukocytes associated with ovarian tumors. The nonapeptide E75 (HER-2, 369-377:KIFGSLAFL) was efficient in sensitizing T2 cells for lysis by all four CTL lines. This peptide was specifically recognized by cloned CD8+ CTL isolated from one of the ovarian-specific CTL lines. E75-pulsed T2 cells inhibited lysis by the same CTL clone of both an HLA-A2+ HER-2high ovarian tumor and a HER-2high cloned ovarian tumor line transfected with HLA-A2, suggesting that this or a structurally similar epitope may be specifically recognized by these CTL on ovarian tumors. Several other HER-2 peptides were recognized preferentially by one or two CTL lines, suggesting that both common and private HER-2 epitopes may be immunogenic in patients with ovarian tumors. Since HER-2 is a self-antigen, these peptides may be useful for understanding mechanisms of tumor recognition by T cells, immunological tolerance to tumor, and structural characterization of tumor antigens.

https://rupress.org/jem/article-pdf/181/6/2109/1106716/2109.pdf

Identification of an immunodominant peptide of HER-2/neu protooncogene recognized by ovarian tumor-specific cytotoxic T lymphocyte lines.

CTL isolated from tumor infiltrating lymphocytes/tumor associated lymphocytes (TAL) infiltrating ovarian tumors have been demonstrated to mediate lysis of tumor targets after in vitro culture. These effector cells are of particular interest as cellular probes to detect and define human tumor Ag and epitopes that stimulate cellular immunity to human tumors. Polymorphic epithelial mucin (PEM) core peptides are potential candidates as tumor specific Ag because of their preferential expression on epithelial tumors. We report here that ovarian CTL-TAL can recognize mucin (Muc-1) core peptide of PEM. Several ovarian CTL-TAL lines were developed that recognized in a non-MHC restricted fashion an Muc-1+ ovarian tumor, but not Muc-1-tumor. To define the specificity of these CTL-TAL and exclude cross-reactivity with other potential Ag, cytotoxicity experiments were performed using as targets EBV-transformed cell lines with an expression construct containing the Muc.1 cDNA. These ovarian CTL-TAL lysed mucin core-peptide transfected cells but not targets transfected with an expression construct containing a mucin frame-shift mutant cDNA as control. In addition, targets pulsed with short synthetic peptides composed of amino acids 1-14 of the Muc 1 core peptide repeat were also lysed by the same CTL-TAL. This lysis was inhibited by the mAb SM3 that recognize an epitope on the mucin core peptide. These results, which are a demonstration of a specific Ag recognized by ovarian CTL-TAL, may be of interest for specific immunotherapy of ovarian cancer.

Cytotoxic T cells from ovarian malignant tumors can recognize polymorphic epithelial mucin core peptides.

Cytotoxic T cells isolated from ovarian malignant ascites recognize a peptide derived from the HER-2/neu proto-oncogene.

Background: Tumor-associated lymphocytes (TAL) isolated from ovarian cancer patients contain cytotoxic T lymphocytes (CTL) capable of recognizing specific HLA/peptide complexes on tumor cells leading to tumor cell lysis. Currently, HER2/neu, overexpressed in only 30% of breast and ovarian cancers, is the only known source of CTL-recognized peptides in epithelial cancers. Therefore, we have investigated peptides derived from folate binding protein (FBP), which is over-expressed in more than 90% of ovarian cancers and in the majority of other epithelial tumors.

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Papers

Identification of an immunodominant peptide of HER-2/neu protooncogene recognized by ovarian tumor-specific cytotoxic T lymphocyte lines.

Cytotoxic T cells from ovarian malignant tumors can recognize polymorphic epithelial mucin core peptides.

Cytotoxic T cells isolated from ovarian malignant ascites recognize a peptide derived from the HER-2/neu proto-oncogene.

Ovarian cancer-associated lymphocyte recognition of folate binding protein peptides.

Oligopeptide Induction of a Cytotoxic T Lymphocyte Response to HER-2/Neu Proto-oncogene in Vitro