Understanding of the mechanisms involved in the induction of immunity and the recognition of antigens by effector cells has improved dramatically in the past decade as molecular biology has joined forces with classic tumor immunology. This improved molecular understanding has led to many new therapeutic approaches. For example, immune responses can be dramatically altered by single amino acid changes in either antigens or receptors.
A tumor-associated antigen (TAA) is an antigen that is relatively restricted to tumor cells. Tumor-specific antigens (TSAs) are antigens unique to tumor cells. The development of tumors despite the presence of antigens, the significance of immune recognition in the pathogenesis of tumors, and the potential for therapeutic augmentation of immune responses are the subjects of intense investigation.
Antigens present on tumor cells but not present or apparent on normal cells.
In animal experiments, most tumors induced or transplanted into syngeneic recipients provide immunity against subsequent challenge with the same tumor but not against challenge with transplanted normal tissues or other tumors. Tumor antigens are particularly well demonstrated by (1) chemical carcinogen-induced tumors, which tend to have specific antigens that vary among tumors, even among tumors induced by the same carcinogen, and by (2) virus-induced tumors, which tend to show cross-reactivity between tumors induced by the same virus. Viral infections may result in “modified self,” ie, new antigens recognized in the context of the major histocompatibility complex (MHC).
Suggested mechanisms of origin for these antigens include (1) new genetic information introduced by a virus, such as human papillomavirus E6 and E7 proteins in cervical cancer; (2) alteration of oncogenes by carcinogens, which either generate a novel protein sequence directly or result in the induction of genes that are normally not expressed (except perhaps during embryonic development); (3) uncovering of antigens normally “buried” in the cell membrane because neoplastic cells are unable to synthesize membrane components (eg, sialic acid); and (4) release of antigens normally sequestered in the cell or its organelles when neoplastic cells die.
Techniques for defining tumor antigens have greatly improved with molecular cloning. Tumor antigens have been directly purified from cancer cells and identified by physicochemical techniques, such as tandem mass spectrometry. Alternatively, tumor-specific T-cell clones can be tested against antigen-negative cells that have acquired antigen by being transfected with plasmid DNA clones to isolate the clone expressing the antigen. Synthetic peptides can then be constructed to precisely identify the antigenic site or epitope.
Some TAAs and TSAs in human cancers have been identified, eg, in Burkitt’s lymphoma, neuroblastoma, malignant melanoma, osteosarcoma, renal cell carcinoma, breast carcinoma, and some GI and lung carcinomas. Choriocarcinomas in women have paternally derived MHC antigens that may function as TSAs in eliciting an immune response, which possibly contributes to the complete cure of these tumors with chemotherapy. Unfortunately, although other human tumors may have antigenic TAAs or TSAs, not all are immunogenic in the host.
Revision date: June 14, 2011
Last revised: by Andrew G. Epstein, M.D.