Tumor Antigens and Immune Surveillance

• Immune surveillance is the host immune system's recognition and destruction of newly appearing tumor cells that are seen as foreign
• Questions to address regarding tumor immunity encompass the nature of tumor antigens, host effector systems that recognize tumor cells, and the effectiveness of tumor immunity against spontaneous neoplasms

Tumor Antigens

• Initially classified by expression patterns, antigens were divided into tumor-specific antigens, present only on tumor cells, and tumor-associated antigens, present on both tumor and some normal cells
• Now, tumor antigens are classified based on molecular structure and source
• Cytotoxic T lymphocytes (CTLs) recognize tumor antigens which has advanced tumor immunology through the development of identification techniques
• CTLs are crucial for the major immune defense mechanism against tumors

Main Classes of Tumor Antigens

• Antigens derived from mutant oncoproteins and tumor suppressor proteins are grouped as products of mutated oncogenes and tumor suppressor genes
• Unique tumor antigens originate from B-catenin, RAS, p53, and CDK4, often due to mutations in their encoding genes
• Peptides are exclusively expressed in tumor cells, as mutant genes are only present in tumors
• Shared antigens exist across different tumors, as many tumors may share mutations
• The HER2/NEU oncogene is a notable example with high expression in some breast cancers
• Clinically, antibodies targeting Her2/Neu protein treat breast cancers
• Some tumor antigens are normal cellular proteins that are abnormally expressed in tumor cells to elicit immune responses
• Some tumor antigens in human melanomas are structurally normal proteins, produced at low levels in normal cells, but overexpressed in tumor cells
• Tyrosinase, an enzyme in melanin biosynthesis, is an antigen expressed only in normal melanocytes and melanomas
• Cancer-testis antigens are encoded by genes silent in normal adult tissues, except the testis
• Proteins produced by oncogenic viruses are recognized as foreign by the immune system
• Proteins from latent DNA viruses are the most potent antigens
• Examples of viruses include HPV and EBV
• Carcinoembryonic antigen (CEA) and alpha-fetoprotein are oncofetal antigens/embryonic antigens expressed during embryogenesis but not in normal adult tissues
• The depression of the genes that encode for these antigens causes their overexpression in colon and liver cancers
• Most experimental and human tumors express higher, or abnormal, levels of surface glycoproteins and glycolipids, making them therapeutic targets and diagnostic markers
• Altered molecules include gangliosides, blood-group antigens, and mucins
• Diagnostic and therapeutic studies have focused on several mucins

-CA-125 and CA-19-9 are expressed on ovarian carcinomas -MUC-1 is expressed on breast carcinomas

• Cell type-specific differentiation antigens are specific for particular lineages or differentiation stages of cell types
• They are potential immunotherapy targets useful in identifying the tissue of origin of tumors
• For example, lymphomas are diagnosed as B cell-derived tumors via the detection of surface markers like CD20
• Antibodies against CD20 are used for the immunotherapy of certain B cell lymphomas

Clinical Aspects of Neoplasia

• Neoplasms affect patients, with problems caused by both malignant and benign tumors
• Location and impingement on adjacent structures leads to problems
• Functional activity, like hormone synthesis, or the development of paraneoplastic syndromes causes problems
• Bleeding and infections can occur if the tumor ulcerates through adjacent surfaces
• Rupture or infarction can lead to symptoms
• Cachexia, or wasting, can occur

Cancer Cachexia

• Patients experience progressive loss of body fat, lean body mass, profound weakness, anorexia, and anemia
• Release of cytokines by the tumor or the host is a cause of cachexia
• Cachexia is not caused by the nutritional demands of the tumor

Paraneoplastic Syndrome

• Systemic symptoms are caused by ectopic production and secretion of bioactive substances (ACTH, PTHrP, TGF-α), not by tumor spread or hormones appropriate to the tissue
• Diverse syndromes are associated with different tumors
• Paraneoplastic syndromes include: -Hypercalcemia -Cushing syndrome -Nonbacterial thrombotic endocarditis
• Lung and breast cancers and hematologic malignancies are most often associated with paraneoplastic syndromes

Laboratory Diagnosis of Cancer

• Diagnosis of cancer includes morphologic and molecular methods
• The specimen must be adequate, representative, and properly preserved in morphologic methods
• Excision or biopsy, fine-needle aspiration, and cytologic smears are several available sampling approaches
• Frozen section is useful in certain situations, such as determining the nature of a mass lesion or in evaluating regional lymph nodes for metastasis
• Histologic evaluation occurs within minutes, as a sample is quick-frozen and sectioned with this method

Fine Needle Aspiration

• Aspiration of cells from a mass is required
• Cytologic examination of the smear follows aspiration of cells from a mass
• Readily palpable lesions require fine needle aspiration on the breast, thyroid, lymph nodes, and salivary glands
• Imaging techniques now permit extension of the method to deeper structures, such as the liver, pancreas, and pelvic lymph nodes
• Cytologic (Papanicolaou) is a diagnostic method
• Immunocytochemistry is a diagnostic method
• Flow cytometry is a diagnostic method
• Tumor markers are diagnostic tumor markers
• Molecular techniques are applied in molecular diagnosis for diagnosis of tumors and for predicting their behavior
• Diagnosis of malignancy, prognosis and behavior, detection of minimal residual disease, diagnosis of hereditary predisposition to cancer, and therapeutic decision-making can all be determined using molecular diagnosis
• Therapies target specific mutations, so detection of such mutations in tumors guide the development of targeted therapy