Host Defense Against Tumor Tumor Immunity

1. Host Defense Against TumorTumor Immunity Definition coordinated biologic process designed to recognize tumor cells and their products and to kill or damage the offending cells.

2. Host Defense Against TumorTumor Immunity Tumor Specific Antigens (TSA) Present only on tumor cells and not on any normal cells and can be recognized by cytotoxic T-lymphocytes. Tumor Associated Antigens (TAA) Not unique to tumors and are also see on normal cells.

3. Tumor Antigens Tumor Specific Antigens (TSA) Cancer testis antigen Viral antigen Mucin Oncofetal antigens Antigens resulting from mutational in protein B catenin, RAS, P53,CDK4

4. Tumor Antigens Tissue Associated Antigen=TAA Present in normal cells & tumor cells e.g. MART-1, gp100, tyrosinase expressed in melanomas & normal melanocytes T-cells directed against melanomas will also destroy normal melanin containing cells

5. Tumor Antigens Tumor Associated Antigens(TAA) MART-1, gp100, tyrosinase Over expressed antigens Differentiation- specific antigens

6. Tumor Associated Antigens(TAA) Over expressed Antigens e.g HER-2 (neu) in 30 % Breast cancer ( present in normal breast & ovary)

8. Tumor Associated Antigens(TAA) Differentiation- Specific Antigens e.g CD10& PSA Expressed in normal B cells & Prostate Used as a marker for tumors arise from these cells

9. ANTITUMOR EFFECTOR MECHANISM Cellular Cytotoxic T lymphocytes. Natural killer cells. Macrophages. Humoral mechanisms.complement mediated or ADCC.

10. Mechanisms of Immunity to Tumors Cytotoxic T lymphocytes (CTL)- that are sensitized to TSA and perhaps other tumor antigens kill tumor cells. Play a role in virus induce malignancy Natural Killer (NK) cells - can attack tumor cells directly without antibody coating or by Antibody Dependent Cell Cytotoxicity (ADCC) utilizing the Fc receptor on the NK cells.

11. Mechanisms of Immunity to Tumors Killer Macrophages - activated by IFN-g elaborated by Helper T lymphocytes. Participate in ADCC and can lyse tumor cells through release of TNF-a.

13. Immune surveillance: a constant monitoring process aimed at eliminating emerging cancers recognition and destruction of non-self tumor cells .

14. Evidence for Immune Response to Tumors 1) Infiltrate of lymphocytes and macrophages associated with better prognosis in many tumors. 2) Peripheral blood NK activity correlates with survival. 3) Peripheral blood lymphocytes counts fall as cancer overwhelms host; patients develop anergy to skin tests.

15. Evidence for Immune Response to Tumors 4) Non-specific vaccines can stimulate macrophages and improve prognosis. IFN-g and IL-2 can stimulate NK cells and improve outcome. 5) High incidence of some tumors in immunosuppressed individuals. 6) Spontaneous regression in some tumors.

16. Sporadic cancers occur in immune competent people HOW ??? Escape mechanisms : Growth of antigen-negative variants. HLA underexpression . No expression of costimulatory molecule . Immunosuppression . Immunosurveillance

18. Clinical Features Of Neoplasia

19. Clinical Features Of Neoplasia Effects of Tumor On Host Grading & Clinical Staging Of Cancer The Laboratory Diagnosis of Cancer

20. Effects of Tumor On Host Tumor Impingement on nearby structures Pituitary adenoma on normal gland---compression of normal tissue -----Hypopitutrism Pancreatic carcinoma on bile duct-----Produce fatal billiary tract obstruction Renal artery leiomyoma-------ischemia & hypertention Hormones production-----B cell tumor produce hyperinsulinism Ulceration/bleeding Colon, Gastric, and Renal cell carcinomas Infection (often due to obstruction) Pulmonary infections due to blocked bronchi (lung carcinoma), Urinary infections due to blocked ureters (cervical carcinoma) Rupture or Infarction Ovarian, Hepatocellular, and Adrenal cortical carcinomas; Melano-carcinoma metastases

21. Effects of tumor on host Cancer Cachexia Paraneoplastic Syndromes Endocrinopathies Neuromyopathies Osteochondral Disorders Vascular Phenomena Fever Nephrotic Syndrome

22. Cancer Cachexia Progressive weakness, loss of appetite, anemia and profound weight loss (>20 lbs.) Often correlates with tumor size and extent of metastases Etiology includes a generalized increase in metabolism and central effects of tumor on hypothalamus Probably related to macrophage production of TNF-a

23. PARANEOPLASTIC SYNDROMESSymptom complexes other than cachexia that appear in patients with cancer and cannot be readily explained either by the local or distal spread of the tumor or by the elaboration of hormones indigenous to the tissue of origin of the tumor . Occur in 10-15% of tumors

25. Paraneoplastic Syndromes Cushing’s Syndrome Small cell undifferentiated lung cancer (ACTH) like product. Nonbacterial thrombotic Endocarditis Hypercoagulability

26. Paraneoplastic Syndromes Hypercalcemia(Cancer is the most common cause of hypercalcemia by either humoral or metastatic mechanisms) Squamous cell carcinoma of lung (PTH-like peptide) Renal cell carcinoma (prostaglandins) Parathyroid carcinoma (PTH) Multiple myeloma and T-cell lymphoma (IL-1 and perhaps TNF-a) Breast carcinoma, usually by bone metastasis

28. Paraneoplastic Syndromes Hypoglycemia - caused by tumor over-production of insulin or insulin like activities Fibrosarcoma, Cerebellar hemangioma, Hepatocarcinoma Carcinoid syndrome - Caused by serotonin, bradykinin or ?histamine produced by the tumor Bronchial carcinoids, Pancreatic carcinoma, Carcinoid tumors of the bowel

29. Paraneoplastic Syndromes Polycythemia -caused by tumor production of erythropoietin's Renal cell carcinoma, Cerebellar hemangioma, Hepatocarcinoma WDHA syndrome(watery diarrhea, hypokalemia, and achlorhydria) - caused by tumor production of vasoactive intestinal polypeptide (VIP). Islet cell tumors, Intestinal carcinoid tumors

30. Paraneoplastic SyndromesNeuromyopathies Myasthenia Gravis-A block in neuromuscular transmission possibly caused by host antibodies against the tumor cells that cross react with neuronal cells or perhaps caused by toxins. Bronchogenic carcinoma, Breast cancer Carcinomatous Myopathy - probably immune-mediated

31. Paraneoplastic SyndromesOsteochondral Disorders Hypertrophic Osteoarthropy - clubbing, periosteal new bone, and arthritis Isolated clubbing occurs in chronic obstructive pulmonary disease and in cyanotic congenital heart disease, but the full-blown syndrome is limited to lung cancer.

33. Paraneoplastic SyndromesVascular Phenomena Altered Coagulability - caused by the release of tumor products Migratory Venous Thromboses (Trousseau’s sign) Pancreatic, gastric, colon, and bronchogenic carcinomas; particularly adenocarcinoma of the lung. Marantic endocarditis - Small thrombotic vegetations on mitral or aortic valves that occur with advanced carcinomas.

35. Paraneoplastic SyndromesFever Associated with bacterial infections Common where blockage of drainage occurs Decreased immunity may play a role Not associated with infection Episodic as in Bar-Epstein fever with Hodgkin's lymphoma; poor prognostic seen in sarcomas, indicates dissemination Likely caused by response to necrotic tumor cells and/or immune response to necrotic tumor proteins.

36. Paraneoplastic SyndromesNephrotic Syndrome Excessive loss of protein in the urine probably caused by damage to renal glomeruli by tumor antigen-antibody complexes.

38. Grading And Staging Grading is based on the microscopic features of the cells which compose a tumor and is specific for the tumor type. Staging is based on clinical, radiological, and surgical criteria, such as, tumor size, involvement of regional lymph nodes, and presence of metastases. Staging usually has prognostic value.

39. Grading Estimate of aggressiveness of tumor or level of malignancy based on -cytological differentiation -number of mitosis Tumors are classified as grad 1,2,3,4 in order of increasing anaplasia

40. In the diagram below utilizing an adenocarcinoma as an example, the principles of grading are illustrated: Grading Staging and Grading

41. Staging Anatomical spread of tumor based on -size of tumor -spread to regional L.N -presence or absence of metastasis TNM staging system & AJC

43. Staging and Grading In this diagram utilizing a lung carcinoma as an example, the principles of staging are illustrated:

44. Diagnostic Methods for Neoplasia History and Physical Examination learning from: talking to the patient . direct examination clues to the presence of a neoplasm. Signs and symptoms such as weight loss, fatigue, and pain may be present. A mass may be palpable or visible.

45. Diagnostic Methods for Neoplasia Radiographic Techniques The use of plain films (x-rays), computed tomography (CT), magnetic resonance imaging (MRI), mammography, and ultrasonography (US) may be very helpful to detect the presence and location of mass lesions. The findings from these methods may aid in staging and determination of therapy.

46. biochemical assays tumor markers: sometimes diagnostic or prognostic can be helpful in monitoring effectiveness of therapy or in detecting relapses/recurrences Serum tumor markers: prostate specific antigen,CEA ,β-HCG ,α-FETOPROTEIN...etc )may help to determine the presence of specific neoplasms . not perfect screening tools in a general population.

47. Laboratory Diagnostic Methods for Neoplasia Laboratory Analyses General findings ( anemia, enzyme abnormalities (alkaline phosphatase,LDH), URIN (hematuria) ,stool occult blood further workup. Detection of specific genes (such as BRCA-1 for breast cancer) may suggest an increased risk for some malignancies.

48. Pathological Diagnostic Procedures FNA (fine needle aspiration) cytological smears biopsy frozen sections

49. Diagnostic Methods for Neoplasia Cytology sample cells simple cost-effective minimally invasive. e.g : Pap smear for the diagnosis of cervical dysplasias and neoplasms. Cells exfoliated into body fluids can be examined. Fine needle aspiration (FNA) can be used also.

50. Pap smear with dysplasia