NEOPLASIA VITumor Host Interactions

Husni Maqboul, M.D

Tumor Host Interactions

Local Effects Cancer Cachexia Paraneoplastic Syndromes

– Endocrinopathies– Neuromyopathies– Osteochondral Disorders– Vascular Phenomena– Fever– Nephrotic Syndrome

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

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

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-and IL-1

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)

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-)– Breast carcinoma, usually by bone metastasis

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

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

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

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.

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.

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.

Paraneoplastic SyndromesNephrotic Syndrome

Excessive loss of protein in the urine– probably caused by damage to renal glomeruli

by tumor antigen-antibody complexes.

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.

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)

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.

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.

Evidence for Immune Response to Tumors-II 4) Non-specific vaccines can stimulate

macrophages and improve prognosis. IFN- 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.

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- which stimulate CTL, macrophages, NK cells and B lymphocytes. They also produce TNF-.

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.

Mechanisms of Immunity to Tumors-II

Killer Macrophages - activated by IFN- elaborated by Helper T lymphocytes. Participate in ADCC and can lyse tumor cells through release of TNF-.

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-. Tumor infiltrating lymphocytes (TIL) are CTL sensitized to the tumor that can be expanded in vitro and reintroduced to the patient.

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.

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.