Tumor antigen

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Tumor antigens are antigens ( Engl. Anti body gen erating ) derived from cancer cells are produced and are able, in the affected organism an immune response trigger. This property makes tumor antigens important target structures in cancer immunotherapy and as tumor markers in diagnostics .

Origin and occurrence

The tumor antigens arise as a result of the genome changed in cancer cells or as a result of a change in gene expression ("switching on and off" genes ). These changes can result in new gene products that are foreign to the body or proteins that are normally only present in the embryonic development phase , for example . Often certain proteins - also present in healthy cells of the body at the time of the illness - are produced ( overexpressed ) in large quantities .

All these properties and mechanisms lead to differences between normal cells and cancer cells, which, however, in the last two examples do not often lead to an immune response , since the gene products are not exogenous.

The tumor antigens can be located in the cell plasma or on the cell membrane or, as a result of antigen shedding, can be freely located in the extracellular space . They are divided into two groups: the tumor-specific antigens ( TSA ), also called neoantigens (neo = "new"), and the tumor-associated antigens ( TAA ). This classification is somewhat idealized, as some “tumor-specific” antigens were later also found in certain normal cells.

Almost all previously known tumor antigens are presented on the cell membrane via the MHC-I complex .

Free tumor antigens that are released into the extracellular space by antigen shedding and then circulate in the blood , for example , are often used as tumor markers in diagnostics .

Tumor Specific Antigens (TSA)

Mutations in the chromosomes of cancer cells can lead to the cancer cell producing novel gene products unknown to the body. These antigens are called tumor-specific because they are only produced by tumors and not by any other healthy body cell. If these gene products (proteins) are presented to the outside world of the cell on the cell membrane via the main histocompatibility complex , the corresponding cancer cell can be recognized as “foreign” by the immune system and destroyed. The cause of the mutations can, for example, splice variants , point mutations , chromosomal rearrangements or by viruses infiltrated oncogenes be.

Since tumor-specific antigens are not present in normal tissue, TSA-specific T lymphocytes in the thymus are not negatively selected. However, the tumor-specific antigens are often only expressed in small numbers by tumor cells and are then not sufficiently presented in competition with normal membrane proteins .

Examples

In almost all patients suffering from chronic myeloid leukemia , there has been a reciprocal translocation of chromosomes 9 and 22 in the region of the genes ABL (chromosome 9 gene locus q34) and BCR (chromosome 22 gene locus q11). The translocation results in the formation of two fusion genes BCR-ABL (on chromosome 22) and ABL-BCR (on chromosome 9). The corresponding gene products are only expressed on the cancer cells and can be recognized as "foreign" by the immune system.

The TP53 gene coding for p53 has been mutated in many tumors. Correspondingly, p53 then has modified protein sequences - that is, tumor-specific antigens - that cannot be found in normal cells.

Tumor Associated Antigens (TAA)

While the tumor-specific antigens are new, foreign proteins that are only produced by cancer cells, the tumor-associated antigens are gene products that are also expressed by healthy cells. In contrast to healthy cells, the tumor-associated antigens are overexpressed in cancer cells and are accordingly often presented on the cell membrane via the main histocompatibility complex. Since these are normal ubiquitous proteins, there is often no immune response. If the antigen density on the cell membrane is high enough, however, the cancer cells can be recognized and destroyed by specific T cells.

Examples

Tyrosinase is an enzyme that is expressed by normal melanocytes . It is highly overexpressed in malignant melanocytes . This enables patients with malignant melanoma to produce T cells that are specific for tyrosinase. In patients with breast cancer or pancreatic tumor, autologous lymphocytes could be detected in the tumor tissue, which specifically reacted against the mucin-1 overexpressed by these tumors .

Types of tumor antigen

Regardless of the idealized division into tumor-specific and tumor-associated, the tumor antigens are divided into different groups depending on their expression pattern:

Differentiation antigens

Differentiation antigens are specific to the tissue from which the tumors arise. For example, they are expressed by normal melanocytes in malignant melanomas . Examples of differentiation antigens are tyrosinases and GP100 .

Over-expressed antigens

Due to increased gene expression, tumor cells can produce (overexpress) proteins - which are also produced by normal cells. Also, post-translational modifications can play a role. Examples of overexpressed tumor antigens are hTERT (a subunit of the enzyme telomerase ) and mucin-1

Cancer / testis antigens

The so-called cancer / testis antigens are only found on cancer cells and in healthy tissue only in the male germ cells and in some cases in the ovaries and trophoblasts . These tumor antigens result from the reactivation of silent genes that are no longer transcribed under normal circumstances . The cause of the reactivation can, for example, be a reciprocal translocation in which the gene comes close to an active promoter .

Since neither MHC-I nor MHC-II is expressed in testicular tissue, these cells are immune-privileged and are not attacked in a therapy aimed at these antigens. All of the genes that code for this group of antigens are found on the X chromosome in humans .

An example of a tumor testis antigen is NY-ESO-1 , which is expressed by many breast, prostate and ovarian cancers. Some authors classify the tumor-testis antigens as tumor-specific antigens.

Mutation antigens

Mutation antigens , also known as structurally altered antigens , are only found in tumor tissue. They are therefore tumor-specific antigens. In most cases they are formed by point mutations in the corresponding genes. Mutation antigens are very often only found in a patient's tumor, since the mutation can be very individual. In these cases one therefore speaks of individual-specific antigens . An exception to this are antigens, in which the mutation is the triggering factor for cancer formation. An example of this is the proto-oncogene Ras .

Oncoviral Proteins

Oncoviral proteins form an independent group of tumor antigens. Examples are the oncoproteins large T antigen of simian virus 40 and E7 of human papillomavirus 16.

Identification of tumor antigens

The identification of tumor antigens with high immunogenicity is one of the greatest challenges for tumor immunology and the key to successful specific immunizations. A rationale in identifying tumor antigens is that their perception by the immune system is an indicator of their relevance in an anti-tumor response. In the past, tumor antigens were identified primarily by analyzing the anti-tumor response in patients. For this purpose, either the peripheral or tumor-infiltrating lymphocytes (TIL) were examined or the humoral immune response was analyzed.

In the meantime, processes have become established that can largely be automated. The two most important methods are SEREX (serological identification of antigens by recombinant expression cloning) and reverse immunology . As a result of the knowledge gained in the context of the human genome project and with the help of improved analytical methods, reverse immunology in particular has been established as a powerful high-throughput method for the identification of tumor antigens for several years .

Important tumor antigens

To date, over 2000 different tumor antigens have been identified. The ideal tumor antigen would be a structure that is only expressed on cancer cells and there in the highest possible number. There is no such antigen. Just as different types of cancer present their own disease patterns, the antigens are expressed depending on the type and type of cancer. The antigen expression can change considerably in the course of the disease through mutation and selection (through therapeutic interventions and the immune system itself) of the cancer cells, even with one type of tumor in a patient.

Therapeutic monoclonal antibodies have been developed for a number of tumor antigens or are still in clinical trials.

Tumor antigens
Tumor-associated antigens

Even if most of the antigens are proteins, cancer cells also show changes in glycolipids and glycoproteins compared to normal cells, which in principle represent target structures for the immune system or therapeutic agents.

history

With MAGEA1 ( melanoma antigen family A, 1 ), the first tumor antigen was discovered in 1991 by Pierre van der Bruggen and colleagues at the Ludwig Institute for Cancer Research in Brussels .

literature

Individual evidence

  1. ↑ A. Dalgleish and H. Pandha: tumor antigens as surrogate markers and targets for therapy and vaccines. In: Adv Cancer Res 96, 2007, pp. 175-190. PMID 17161680 (Review).
  2. ↑ dkfz: The immune system: Has it failed in cancer patients? ( Memento of the original from August 31, 2009 in the Internet Archive ) Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. dated August 7, 2003. @1@ 2Template: Webachiv / IABot / www.krebsinformationsdienst.de
  3. ↑ a b c d e K. Kokowski: Cellular immune response against the tumor antigens mucin and telomerase in patients with breast cancer. Dissertation, FU Berlin, 2008.
  4. ↑ a b c d e S. Höpner: Characterization of a hABL-specific CD4 + T cell response and the use of AdEtOH as a catalyst for peptide loading. Dissertation, FU Berlin, 2008.
  5. ↑ I. Schuster: Identification, cloning and retroviral transfer of allorestricted FMNL1-peptide-specific T-cell receptors for the development of adoptive immunotherapy against B-cell non-Hodgkin lymphomas. (PDF file; 1.28 MB) Dissertation, Ludwig Maximilians University Munich, 2008
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  12. ↑ A. Girling et al .: A core protein epitope of the polymorphic epithelial mucin detected by the monoclonal antibody SM-3 is selectively exposed in a range of primary carcinomas. In: Int J Cancer 43, 1989, pp. 1072-1076. PMID 2471698
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  18. ↑ KR Jerome et al .: Cytotoxic T-lymphocytes derived from patients with breast adenocarcinoma recognize an epitope present on the protein core of a mucin molecule preferentially expressed by malignant cells. In: Cancer Res 51, 1991, pp. 2908-2916. PMID 1709586
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  23. ↑ ME Ressing et al: Human CTL epitopes encoded by human papillomavirus type 16 E6 and E7 identified through in vivo and in vitro immunogenicity studies of HLA-A * 0201-binding peptides. In: J Immunol 154, 1995, pp. 5934-5943. PMID 7538538
  24. ↑ M. Schirle: Identification of disease-associated MHC ligands by mass spectrometric methods.  ( Page no longer available , search in web archives )  Info: The link was automatically marked as defective. Please check the link according to the instructions and then remove this notice. Dissertation, Eberhard-Karls-Universität Tübingen, 2001.@1@ 2Template: Toter Link / w210.ub.uni-tuebingen.de  
  25. ↑ S. Viatte include: reverse immunology approach for the identification of CD8 T-cell-defined antigens: Advantages and hurdles. In: Immunology and Cell Biology 84, 2006, pp. 318-330. PMID 16681829 doi : 10.1111 / j.1440-1711.2006.01447.x (Review).
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  27. ↑ a b P. van der Bruggen et al: A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma. In: Science 254, 1991, pp. 1643-1647. PMID 1840703
  28. ↑ Y. Kawakami et al: Identification of the immunodominant peptides of the MART-1 human melanoma antigen recognized by the majority of HLA-A2-restricted tumor infiltrating lymphocytes. In: J Exp Med 180, 1994, pp. 347-352. PMID 7516411
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  31. ↑ M. Schwarz: Identification of potentially immunogenic peptides on cells of chronic myeloid leukemia. Dissertation, FU Berlin, 2004.
  32. ↑ F. Yang and XF Yang: New concepts in tumor antigens: their significance in future immunotherapies for tumors. (PDF file; 245 kB) In: Cell Mol Immunol 2, 2005, pp. 331-341. PMID 16368059 (Review).