Many tumor cells produce antigens, which may be released in the bloodstream or remain on the cell surface. Any molecule capable of being recognized by the immune system is considered an antigen. Antigens have been identified in most of the human cancers, including Burkitt lymphoma Burkitt Lymphoma Burkitt lymphoma is an aggressive B-cell non-Hodgkin lymphoma occurring in children and adults. Endemic (African), sporadic (non-African), and immunodeficiency-related forms exist. (See also... read more 
, neuroblastoma Neuroblastoma Neuroblastoma is a cancer arising in the adrenal gland or less often from the extra-adrenal sympathetic chain, including in the retroperitoneum, chest, and neck. Diagnosis is confirmed by biopsy... read more , melanoma Melanoma Malignant melanoma arises from melanocytes in a pigmented area (eg, skin, mucous membranes, eyes, or central nervous system). Metastasis is correlated with depth of dermal invasion. With spread... read more 
, osteosarcoma Osteosarcoma (osteogenic sarcoma) Primary malignant bone tumors are much less common than metastatic bone tumors, particularly in adults. Primary malignant bone tumors include multiple myeloma, osteosarcoma, adamantinoma, chondrosarcoma... read more 
, renal cell carcinoma Renal Cell Carcinoma Renal cell carcinoma (RCC) is the most common renal cancer. Symptoms can include hematuria, flank pain, a palpable mass, and fever of unknown origin (FUO). However, symptoms are often absent... read more , breast cancer Breast Cancer Breast cancers are most often epithelial tumors involving the ducts or lobules. Most patients present with an asymptomatic mass discovered during examination or screening mammography. Diagnosis... read more 
, prostate cancer Prostate Cancer Prostate cancer is usually adenocarcinoma. Symptoms are typically absent until tumor growth causes hematuria and/or obstruction with pain. Diagnosis is suggested by digital rectal examination... read more , lung carcinoma Lung Carcinoma Lung carcinoma is the leading cause of cancer-related death worldwide. About 85% of cases are related to cigarette smoking. Symptoms can include cough, chest discomfort or pain, weight loss... read more 
, and colon cancer Colorectal Cancer Colorectal cancer is extremely common. Symptoms include blood in the stool and change in bowel habits. Screening using one of several methods is recommended for appropriate populations. Diagnosis... read more 
. A key role of the immune system is detection of these antigens to permit subsequent targeting for eradication. However, despite their foreign structure, the immune response to tumor antigens varies and is often insufficient to prevent tumor growth (see also Host Response to Tumors Host Response to Tumors The immune response to foreign antigens consists of Humoral mechanisms (eg, antibodies) Cellular mechanisms (See also Tumor Antigens.) Most humoral responses cannot prevent tumor growth. However... read more ).
Tumor-associated antigens (TAAs) are relatively restricted to tumor cells.
Tumor-specific antigens (TSAs) are unique to tumor cells.
TSAs and TAAs typically are portions of intracellular molecules expressed on the cell surface as part of the major histocompatibility complex. However, several antigens with selective expression on the surface of tumor cells are not associated with the major histocompatibility complex and may be candidates for therapeutic targeting. Some examples include
Mesothelin, which is broadly overexpressed on various malignant tumor cells, while its expression is generally limited to normal mesothelial cells
Claudin 18.2, which is expressed in a significant proportion of gastric cancers as well as in the proportion of pancreatic, esophageal, ovarian, and lung tumors
Suggested mechanisms of origin for tumor antigens include
Introduction of new genetic information from a virus (eg, human papillomavirus E6 and E7 proteins in cervical cancer)
Alteration of oncogenes or tumor suppressor genes by carcinogens, which result in formation of neoantigens (novel protein sequences or accumulation of proteins that are normally not expressed or are expressed at very low levels, such as ras or p53), either by generating the novel protein sequence directly or by inducing accumulation of these proteins
Development of missense mutations in various genes not directly associated with tumor suppressor or oncogenes and that cause appearance of tumor-specific neoantigens on the cell surface
Development of abnormally high levels of proteins that normally are present at substantially lower levels (eg, prostate-specific antigens, melanoma-associated antigens) or that are expressed only during embryonic development (carcinoembryonic antigens)
Uncovering of antigens normally buried in the cell membrane because of defective membrane homeostasis in tumor cells
Release of antigens normally sequestered within the cell or its organelles when tumor cells die
Some evidence links the immune response in cancer patients to mutations in tumor cells (1–4 References Many tumor cells produce antigens, which may be released in the bloodstream or remain on the cell surface. Any molecule capable of being recognized by the immune system is considered an antigen... read more ).
References
1. Ding L, Chen F: Predicting tumor response to PD-1 blockade. N Engl J Med 381(5):477–479, 2019. doi: 10.1056/NEJMcibr1906340
2. Keskin DB, Anandappa A, Sun J, et al: Neoantigen vaccine generates intratumoral T cell responses in phase Ib glioblastoma trial. Nature 565:234–239, 2019. doi: 10.1038/s41586-018-0792-9
3. Snyder A, Makarov V, Merghoub T, et al: Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med 37:2189–2199, 2014. doi: 10.1056/NEJMoa1406498
4. Van Allen EM, Miao D, Schilling B, et al: Genomic correlates of response to CTLA-4 blocker in metastatic melanoma. Science 350:207–211, 2015. doi: 10.1126/science.aad0095
