Cancer Immune Therapy Edited by G. Stuhler and P. Walden ...

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of B lymphocytes and plasma cells in the tumor specimens used for the cDNA library, may represent more than 90 % of all ªpositiveº clones in libraries derived from certain tissues. They can be identified by a modified initial screening procedure whereby the nitrocellulose membrane is incubated with enzyme-conjugated anti-human IgG followed by visualization with the appropriate enzymatic color reaction prior to the incubation of the autologous patient's serum [8]. Screening of tumor cell lines rather than fresh tumor specimen circumvents this problem and additionally provides a pure RNA source which is not contaminated with normal stroma [9]. Subtractive approaches allowenriching the cDNA library for tumor-specific transcripts [10]. cDNA libraries may also be prepared from sources of specific interest, such as amplified chromosomal regions obtained by microdissection [11]. 2.3 Searching for Human Antigens by SEREX Expression libraries were constructed and analyzed by SEREX from a variety of different neoplasms, including three different renal cell carcinomas of the clear cell type, two melanomas, one ovarian carcinoma, one hepatocarcinoma, 10 gliomas, two colorectal cancers, one pancreatic cancer, two breast cancers, two Hodgkin's lymphomas, two acute T cell leukemias and two acute myelogenous leukemias. Primary libraries with at least 1 × 10 6 independent clones were established. The screening of at least 1 × 10 6 clones per library revealed multiple reactive clones in each library. Some transcripts were detected repeatedly, indicating that they were multiply represented in the library. In order to bias for the detection of antigens of the cancer testis class, libraries were constructed from normal testis tissue and screened with allogeneic tumor patients' sera. 2.4 Molecular Characterization of SEREX Antigens 2.4 Molecular Characterization of SEREX Antigens Clones were selected for more in-depth analysis on the basis of: 1. Their sequence data and comparison with databases to reveal identity or homologies with known genes and to identify domains or motifs informative for a putative function or cellular localization. 2. The analysis of the expression pattern of the respective antigen in normal tissues and tumors by RT-PCR, by Northern blot hybridization with specific probes and by analysis in expressed sequence tag-containing databases. 3. An initial survey for antibodies in the sera from healthy controls and allogeneic tumor patients to evaluate the incidence of serum antibodies to the respective antigen. Four different groups of genes coding for antigens were identified. The first group codes for known tumor antigens such as the melanoma antigens MAGE-1, MAGE-4a 19
20 2 Serological Determinants On Tumor Cells and tyrosinase. A second group encodes known classical autoantigens for which immunogenicity is associated with autoimmune diseases, e.g. anti-mitochondrial antibodies or antibodies to U1-snRNP. When patients known to have autoimmune or rheumatic disorders are excluded from SEREX analysis, the incidence of such antigens is not higher than 1%. A third group codes for transcripts that are either identical or highly homologous to known genes, but have not been known to elicit immune responses in humans. Examples are restin, which had originally been identified by a murine monoclonal antibody specific for Hodgkin and Reed-Sternberg cells, and lactate dehydrogenase, an enzyme overexpressed in many human tumors. The fourth group of serologically defined antigens represents products of previously unknown genes. 2.5 Specificity of SEREX Antigens According to their expression pattern in normal and malignant tissues, several classes of tumor antigens can be distinguished (Tab. 2.1): (1) shared tumor antigens, (2) differentiation antigens, products of (3) mutated, (4) viral, (5) overexpressed and (6) amplified genes, as well as (7) splice variants, (8) widely expressed, but cancer-associated autoantigens, the immunogenicity of which is restricted to cancer patients, (9) common autoantigens to which antibodies are found in sera from patients with other than malignant diseases, and, finally, (10) products of genes which are underexpressed in the autologous tumor compared to normal tissues. Tab. 2.1 Specificity of tumor antigens detected by SEREX Specificity Example Source (1) Shared tumor antigens HOM-MEL-40 melanoma (2) Differentiation antigens HOM-MEL-55 (tyrosinase) melanoma (3) Mutated genes NY-COL-2 (p53) colorectal carcinoma (4) Splice variants HOM-HD-397 (restin) Hodgkin's disease (5) Viral antigens HOM-RCC-1.14 (HERV-K10) renal cell cancer (6) Overexpression HOM-HD-21 (galectin-9) Hodgkin's disease (7) Gene amplifications HOM-NSCLC-11 (eIF-4g) lung cancer (8) Cancer-related autoantigens HOM-MEL-2.4 (CEBP) melanoma (9) Cancer-independent autoantigens NY-ESO-2 (U1-snRNP) esophageal carcinoma (10) Underexpressed genes HOM-HCC-8 hepatocellular carcinoma 2.5.1 Shared Tumor Antigens Shared tumor antigens are expressed in a variable proportion of human tumors (10± 70 %, depending on the type of tumor). Interestingly, all human shared tumor antigens identified to date are expressed in a variety of human cancers, but not in nor-
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Cancer Immune Therapie: Current and
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Editors: Dr. Gernot Stuhler Univers
Page 5 and 6: VI Preface Recent years have seen a
Page 7 and 8: VIII Contents 2.5.3 Antigens Encode
Page 9 and 10: X Contents 6.4.2 Natural Killer (NK
Page 11 and 12: XII Contents 9.6 Loading DC with An
Page 13 and 14: XIV Contents 14.2.2.1 Cancer-specif
Page 15 and 16: List of Contributors Richard Bucala
Page 17 and 18: Color Plates Fig. 5.2 The MHC class
Page 19 and 20: Fig. 5.5 Different immune effector
Page 21 and 22: Fig. 5.17 Possible pathway for the
Page 23 and 24: Fig. 6.2 T lymphocytes in the tumor
Page 25 and 26: Index a acidic and basic fibroblast
Page 27 and 28: ±, see also tumors cationic lipids
Page 29 and 30: e EBV see Epstein-Barr virus EDR se
Page 31 and 32: immature Mo-DCs 184 immune cells ±
Page 33 and 34: MHC class I antigen-processing mach
Page 35 and 36: ±, onco- 209 ±, over-expressed ce
Page 37 and 38: TICD see tumor-induced cell death T
Page 39 and 40: Part 1 Tumor Antigenicity Cancer Im
Page 41 and 42: 4 1 Search for Universal Tumor-Asso
Page 47 and 48: 10 1 Search for Universal Tumor-Ass
Page 55: 18 2 Serological Determinants On Tu
Page 59 and 60: 22 2 Serological Determinants On Tu
Page 67 and 68: 30 Cancer Immune Therapie: Current
Page 69 and 70: 32 3 Processing and Presentation of
Page 77 and 78: 40 Cancer Immune Therapie: Current
Page 79 and 80: 42 4 T Cells In Tumor Immunity cult
Page 81 and 82: 44 4 T Cells In Tumor Immunity cell
Page 83 and 84: 46 4 T Cells In Tumor Immunity to T
Page 85 and 86: 48 4 T Cells In Tumor Immunity Alth
Page 87 and 88: 50 4 T Cells In Tumor Immunity Tab.
Page 89 and 90: 52 4 T Cells In Tumor Immunity rest
Page 91 and 92: 54 4 T Cells In Tumor Immunity 53 T
Page 93 and 94: Part 2 Immune Evasion and Suppressi
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72 5 Major Histocompatibility Compl
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96 6 Immune Cells in the Tumor Micr
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98 6 Immune Cells in the Tumor Micr
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100 6 Immune Cells in the Tumor Mic
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Tab. 7.1 Effects of tumor-derived m
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122 7 Immunosuppresive Factors in C
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156 8 Interleukin-10 in Cancer Immu
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Part 3 Strategies for Cancer Immuno
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180 9 Dendritic Cells and Cancer: P
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204 Cancer Immune Therapie: Current
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206 10 The Immune System in Cancer:
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232 11 Hybrid Cell Vaccination for
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254 12 Principles and Strategies Em
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270 13 Applications of CpG Motifs f
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288 14 The T-Body Approach: Towards
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300 15 Bone Marrow Transplantation
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312 16 Immunocytokines: Versatile M
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348 17 Immunotoxins and Recombinant
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382 Glossary tion to the variable d
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384 Glossary suppressor gene produc
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386 Glossary press the proper recep
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388 Glossary gp96 See Chaperone. Gr
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390 Glossary cytes and addressing l
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392 Glossary T bodies are being tes
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