Lecture_22_(P).pdf

Tumor Immunity Tumor antigens are of two types: ◦ TTA-tumor associated antigens; present on tumor cells and also on normal cells. ◦ TSA- Tumor Specific Antigens; present only on tumor cells and not on any normal cells. ◦ This classification, however, is imperf...

Tumor Immunity Tumor antigens are of two types: ◦ TTA-tumor associated antigens; present on tumor cells and also on normal cells. ◦ TSA- Tumor Specific Antigens; present only on tumor cells and not on any normal cells. ◦ This classification, however, is imperfect, because many antigens thought to be tumor specific turned out to be expressed by some normal cells as well. Therefore tumor antigens can rather be classified as: ◦ products of mutated proto-oncogenes and tumor suppressor genes ◦ overexpressed or aberrantly expressed cellular proteins ◦ tumor antigens produced by oncogenic viruses ◦ oncofetal antigens ◦ altered cell surface glycolipids and glycoproteins ◦ cell type–specific differentiation antigens.  Tumor Immunity The modern classification of tumor antigens is based on 1. Products of mutant proto-oncogenes or mutant tumor suppressor genes. e.g. products of mutant RAS, BCR/ABL, p53, and CDK4 genes. 2. Over expressed normal cellular proteins, tumour antigens are structurally normal proteins but over expressed or aberrantly expressed in tumor cells compared to normal cells. e.g. Tyrosinase in melanoma cancer-testis antigens, are encoded by genes that are silent in all normal adult tissues except the testis, and are deregulated in cancer cells—hence their name.  Tumor Immunity 3. Onco-fetal antigens: or embryonic antigens, expressed during embryogenesis but not in normal adult tissues. Re-expressed in tumor cells e.g. carcinoembryonic antigen (CEA) and α-fetoprotein are re-expressed in colon and liver cancers respectively. Although they are not entirely tumor specific, they can serve as serum markers in cancer 4. Altered cell surface glycoproteins: Tumor cells may express higher than normal or altered form of cell surface proteins. They can be used as diagnostic markers & for targeted therapy. e.g. CA125 expressed in ovarian Ca and MUC-1 in breast cancer  Tumor Immunity 5. Cell Type-Specific Differentiation Antigens: Tumors express molecules that are normally present on the cells of origin. i.e. Lineage markers These antigens are called differentiation antigens, as specific for particular lineages or differentiation stages of cell types. These are potential targets for immunotherapy and in identifying the tissue of origin of tumors. ◦ e.g. lymphoma is diagnosed as B-cell-derived based on detecting cell surface markers characteristic of B-cell lineage, such as CD20. ◦ Antibodies against these molecules are also used for tumor immunotherapy. i.e. rituximab as anti-CD20 ◦ These differentiation antigens are typically normal self-antigens, and do not induce immune responses in tumor-bearing hosts.  Immune Surveillance ◦ Immune Surveillance: tumor cells can be recognized by the immune system as non-self and destroyed. ◦ Anti tumor activity is predominantly mediated by Cell- mediated mechanisms ◦ CTL-Cytotoxic T (CD8) lymphocytes major immune defense ◦ Natural Killer Cells, first line cells ◦ Macrophages ◦ Increased frequency of Ca in immunocompromised patients  Failure of immune surveillance How cancer cells evade immune surveillance in immuno- competent hosts? Selective out growth of antigen negative variants During tumor progression, strongly immunogenic subclones may be eliminated Loss or reduced expression of histocompatibility molecules Tumor cells may fail to express HLA class I, escaping attack by CTLs. However, may trigger death by NK cells. Immunosuppression ◦ Many oncogenic agents (e.g., chemicals and ionizing radiation) suppress host immune responses. ◦ Tumors or tumor products also may be immunosuppressive.  Effects of Tumor on Host Benign and malignant neoplasms may cause problems because of: 1. Location & pressure effects on adjacent tissues 2. Functional activity, hormone production ◦ e.g. tumors of the adrenal cortex secrete corticosteroids. 3. Ulcerations with bleeding and secondary infection. 4. Acute symptoms due to rupture or infarction. 5. Cachexia. 6. Paraneoplastic syndrome.  Effect of a Tumor on the Host Cachexia Wasting of the whole body due to loss of body fat and body mass along with generalized weakness, anemia, anorexia due to cytokines secreted by tumor cells and host Because of tumor necrosis factor (TNF) secreted by macrophages, which suppresses appetite and inhibits lipases, so blocking the release of fatty acids and inducing proteolysis – from skeletal muscles by activating ubiquitin proteosome pathway.  Paraneoplastic Syndrome Symptom complexes that occur in patients with cancer and that cannot be readily explained by local or distant spread of the tumor or by the elaboration of hormones appropriate for the tumor. ◦ Occur in 10-15% of patients with malignant disease. ◦ Can be the first manifestation of an occult neoplasm. ◦ May be lethal. ◦ Common in lung, breast Ca and hematologic malignancies ◦ Most common syndromes are  Hypercalcemia, Cushing syndrome, & non bacterial thrombotic endocarditis  Caused by ectopic production & secretions.  Grading, and Staging of Tumors ◦ Methods to quantify extent & spread of tumors ◦ Helpful for prognosis Grading of a cancer is based on microscopic features ◦ Degree of differentiation of tumor cells ◦ Number of mitoses. Grading : ◦ Grade I : low grade: well-Differentiated ◦ Grade II : moderate ◦ Grade II & III: poorly differentiated ◦ Grade IV/ High grade: undifferentiated/ Anaplastic Grading and staging Staging of cancer is based on: ◦ the size of the primary lesion-T ◦ extent of spread to lymph nodes-N ◦ presence of metastases -M Staging: clinical, radiological, and surgical assessments Staging has more prognostic value.  Staging of Tumors: ◦ Two international systems,Tumor, node, metastases (TNM) and American joint committee on cancer (AJC), ◦ Cancers are categorized into stages 0-IV ◦ TNM: Tumor, node, metastases T1,T2, T3,T4: based on size of tumor N0, N1,N2: progressively advancing node involvement, M0, M1: presence or absence of metastases. ◦ AJC: American joint committee on cancer categorized into stages 0-IV, ◦ Stage I: Growth is restricted to primary site. ◦ Stage IV: Tumor metastasized extensively. ◦ Stage II & III: in between stage I and IV.  Lab Diagnosis of Tumors: Morphological Methods: ◦ Microscopic diagnosis of tumors received in the lab as: ◦ excisional biopsy, fine needle aspiration biopsy, cytological smear, fresh sample for frozen section diagnosis intraoperatively Tumor markers: ◦ Biochemical assays of tumor associated hormones & other tumor markers in blood or serum which contribute to diagnosis, assessment of effectiveness of treatment & tumor recurrence. Molecular Diagnosis: ◦ by PCR, FISH & Molecular Profiling of Tumors (DNA-microarray analysis)  Applications of Molecular analysis in cancer patients Diagnosis of malignancy: By detecting specific gene mutation, translocation, or surface markers Prognosis & behavior Some gene alterations are associated poor prognosis Analysis of Her2/Neu gene in breast Ca provides prognostic & therapeutic information Detection of minimal residual disease Leftover tumor cells after completion of therapy Detect hereditary predisposition to cancer: germ line mutations such as BRCA-1 increase the risk for development of breast Ca in families