Host Defense against Tumors—Tumor Immunity
- not entirely self and may be recognized by the immune system was conceived by Paul Ehrlich.
- Lewis Thomas and Macfarlane Burnet immune surveillance,
Supported by many observation:
- lymphocytic infiltrates around tumors and in LN draining site
- experimental results, mostly with transplanted tumors;
- ↑ incidence in immunodeficient individuals;
- demonstration of tumor-specific T cells and antibodies in patients.
- Cancers occur in immunocompetent individuals --> immune surveillance is imperfect.
Term cancer immunoediting
- preventing tumor formation
- “sculpting” the immunogenic properties of tumors to select tumor cells that escape immune elimination.
- What is the nature of tumor antigens?
- What host effector systems may recognize tumor cells?
- Is antitumor immunity effective against spontaneous neoplasms? Can immune reactions against tumors be exploited for immunotherapy?
Tumor Antigen
- Tumor-specific Ag (TSA) --> only tumor cells, normal(- )
- Tumor-associated Ag (TAA) --> tum cells & normal cell
- The early attempts to purify and characterize tumor antigens relied on producing monoclonal antibodies specific for tumor cells and defining the antigens that these antibodies recognized. advance
- development of techniques for identifying tumor antigens that were recognized by cytotoxic T lymphocytes (CTLs)
- CTLs are the major immune defense mechanism >< tumors.
- TSA (peptides within tumor cells) --> presented --> surface by Class I MHC --> cytotoxic T-cell response
Products of Mutated Genes
- genetic alterations in proto-oncogenes and tumor suppressor genes; never been seen by the immune system --> recognized as non-self.
- Some cancer patients have circulating CD4+ and CD8+ T cells that can respond to the products of mutated oncogenes such as RAS, p53, and BCR-ABL proteins.
- immunization with mutated RAS or p53 proteins --> CTLs and rejection responses against tumors expressing these mutants.
Overexpressed or Aberrantly Expressed Cellular Proteins.
- Tumor antigens may be normal cellular proteins that are abnormally expressed in tumor cells and elicit immune responses.
- human melanomas some tumor antigens are structurally normal proteins that are produced at low levels in normal cells and overexpressed in tumor cells.
- One such antigen is tyrosinase: melanin biosynthesis that is expressed only in normal melanocytes and melanomas.
- T cells recognize peptides derived from tyrosinase --> tyrosinase vaccines may stimulate such responses to melanomas; clinical trials with these vaccines are ongoing
- “cancer-testis” ag: silent in all adult tissues except the testis Although the protein is present in the testis it is not expressed on the cell surface in an antigenic form, because sperm do not express MHC class I antigens --> tumor specific.
- detected in other tumors.
- Prototypic of this group is the melanoma antigen gene (MAGE)
- family. Although originally described in melanomas, MAGE antigens are expressed by a variety of tumor types. For example, MAGE-1 is expressed on 37% of melanomas and a variable number of lung, liver, stomach, and esophageal carcinomas.[180] Similar antigens called GAGE, BAGE, and RAGE have been
- viruses produce proteins --> recognized as foreign by the immune system.
- The most potent of these antigens <-- latent DNA viruses: HPV and EBV.
- vaccines against HPV antigens are effective in preventing cervical cancers in young females.
Oncofetal Antigens.
- silenced during development and are derepressed upon malignant transformation.
- increased in tissues and in the circulation in various inflammatory conditions, and they are found in small quantities even in normal tissues.
- evidence that oncofetal antigens are important inducers or targets of antitumor immunity.
- The two most thoroughly characterized oncofetal antigens are carcinoembryonic antigen (CEA) and α-fetoprotein (AFP) --> “Tumor Markers”.
0 komentar:
Post a Comment