NEOPLASIA VI Tumor Host Interactions

1. NEOPLASIA VITumor Host Interactions Husni Maqboul, M.D

3. Tumor Host Interactions • Local Effects • Cancer Cachexia • Paraneoplastic Syndromes • Endocrinopathies • Neuromyopathies • Osteochondral Disorders • Vascular Phenomena • Fever • Nephrotic Syndrome

4. Local Effects • Tumor Impingement on nearby structures • Pituitary adenoma on normal gland, Pancreatic carcinoma on bile duct, Esophageal carcinoma on lumen • Ulceration/bleeding • Colon, Gastric, and Renal cell carcinomas

5. Local Effects • 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

6. 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 and IL-1

7. Paraneoplastic SyndromesEndocrinopathies • Cushing’s Syndrome • Adrenal carcinoma (cortisol) more common with benign adrenal processes. • Small cell undifferentiated lung cancer (ACTH) released through cleavage of pro-opiomelano-cortin gene product. • Inappropriate ADH syndrome (Hyponatremia) • Small cell undifferentiated lung cancer (vassopressin-like hormone. • Hypothalamic tumors (vasopressin)

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

10. Paraneoplastic SyndromesEndocrinopathies • 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

11. Paraneoplastic SyndromesEndocrinopathies • Polycythemia - caused by tumor production of erythropoietins • 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

12. Paraneoplastic SyndromesNeuromyopathies • Myasthenia - 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

13. 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.

15. 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.

17. 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 Pel-Ebstein fever with Hodgkin’s lymphoma; poor prognostic sign in sarcomas, indicates dissemination • Likely caused by response to necrotic tumor cells and/or immune response to necrotic tumor proteins.

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

19. Host Defense Against TumorsImmune Response to Tumor Antigens • Definition - coordinated biologic process designed to recognize tumor cells and their products and to kill or damage the offending cells.

20. Host Defense Against TumorsImmune Response to Tumor Antigens • Tumor Specific Antigens (TSA) are present only on tumor cells and not on any normal cells and can be recognized by cytotoxic T-lymphocytes. • Cancer-Testis Antigens : MAGE in melanoma, lung, liver, stomach, GAGE, BAGE, RAGE • Tissue specific antigens : MART1 on normal melanocytes and melanoma • Mutational antigens : products of mutated RAS, TP53, β-catenin • Overexpressed antigens : (not recognized normally because of low concentration ) HER-2 protein in breast carcinoma • Viral antigens : HPV, EBV • Mucins : underglycosylation of tumor mucin product reveals epitopes that were covered by carbohydrates (MUC-1)

21. Host Defense Against TumorsImmune Response to Tumor Antigens • Tumor Associated Antigens (TAA) are not unique to tumors. • Tumor-associated carbohydrate antigens • Oncofetal antigens • Expressed in embryogenesis, but not in adult tissue ( CEA, AFP) • Differentiation-specific antigens • CD10 : on neoplastic and normal B-cells • PSA : on normal and neoplastic prostatic epithelial cells • Not helpful for tumor rejection but useful for diagnosis and therapy.

23. Evidence for immune response to tumors-I • Immune surveillance: a constant monitoring process aimed at eliminating emerging cancers. • Evidence for immune response to tumor • 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.

24. Evidence for Immune Response to Tumors-II • 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 immunosupressed individuals. • 6) Spontaneous regression in some tumors. • 7) Experimental animals cured of tumor reject rechallenge by the tumor.

26. Mechanisms of Immunity to Tumors-I • Cytotoxic T lymphocytes (CTL) - that are sensitized to TSA and perhaps other tumor antigens kill tumor cells. • Helper T lymphocytes - release IL-2 and IFN-g which stimulate CTL, macrophages, NK cells and B lymphocytes. They also produce TNF-a. • 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.

27. Mechanisms of Immunity to Tumors-II • Killer Macrophages - activated by IFN-g elaborated by Helper T lymphocytes. Participate in ADCC and can lyse tumor cells through release of TNF-a. • B lymphocytes/Plasma cells - Produce antibody directed against tumor antigens that can kill tumor cells by complement activation. • Lymphokine Activated Killer (LAK) Cells - CTL and NK cells from the tumor activated by IL-2 and IFN-g. Tumor infiltrating lymphocytes (TIL) are CTL sensitized to the tumor that can be expanded in vitro and reintroduced to the patient.

29. Mechanisms of Tumor Resistance to Immune Response-I • Many human tumors are weakly antigenic • Reduced expression of HLA-I • Elimination of strongly immumogenic clones • Lack of costimulation • Blocking antibodies obscure tumor associated antigens (TAA). • Shed tumor antigens tie up receptors on ADCC mediating cells. • Large tumor burden produces so much TAA that tolerance develops.

30. Mechanisms of Tumor Resistance to Immune Response-II • Antigenic evolution occurs as tumor progresses. • Genetic inability of host to respond to certain antigens. • Immunosuppression • Some tumors produce TGF-β • Increase of suppressor T-cells • Protein calorie malnutrition resulting from the tumor reduces immune response.