CARCINOGENIC AGENTS AND TUMOR IMMUNOLOGY DAVID LEWIN MD

OVERVIEW Three Classes of Carcinogens

Chemical Radiation Viral

Tumor Immunology Tumor Antigens Antitumor Effector Mechanisms Immunosurveillance Immunotherapy

CHEMICAL CARCINOGENS Natural and Synthetic Agents Highly reactive electrophiles

(electron deficient) React with RNA, DNA or cellular

proteins Direct –Acting Indirect-Acting

CHEMICAL CARCINOGENS

Direct Acting Agents Weak carcinogens Require no chemical transformation

Chemotherapeutic drugs Alkylating agents

Cyclophosphamide, chlorambucil, nitrosoureas Second malignancy decades later

Acylating agents 1-Acetyl-imidazole, Dimethylcarbamyl

chloride

Indirect Agents Require metabolic conversion before they become active.

Procarcinogen- initial chemical Ultimate carcinogen: active end product

Examples Polycyclic hydrocarbons: fossil fuels, active epoxides bind DNA

Benz[a]anthracene: skin cancer Benzo[a]pyrene: cigarette smoke- lung cancer

Indirect Agents Continued Examples

Aromatic amines and azo dyes Converted in liver by P-450

Beta-naphthylamine: Bladder ca in rubber factories Azo dyes: developed for food color

Nitrosamines and amides Formed endogenously in acid environment of

stomach GI cancers?

Aflatoxin B Aspergillus in grains

Hepatocellular cancer

Mechanism of Action of Chemical Carcinogens Mutagenic

Ras mutations in rodents Promoter

Augmenting agents by themselves not carcinogenic

Produce cell proliferation Must follow mutagenic chemical “initiator”

Tetra-decanoylphorbol-acetate (TPA) Activate protein kinase C

Patients at High risk Genetic disorders i.e.. HNPCC

Radiation Carcinogenesis Types of radiation

Ultraviolet rays of sunlight

Melanoma, Squamous cell carcinoma, basal cell carcinoma

X-rays Early developers: skin

cancer ENT ca with irradiation:

thyroid cancer Nuclear fission

Survivors of nuclear bomb: leukemia

Radionuclides Miners: lung cancer Ionizing radiation: chromosome breakage,

translocations and point mutations

MECHANISMS OF VIRAL CARCINOGENESIS

ONCOGENES Carry oncogenes in viral DNA

INSERTIONAL MUTAGENESIS Altering structure and/or function of

host genome.

TUMOR VIRUSES

RNA VIRUSES (RETROVIRUSES) DNA VIRUSES Important for both types of viruses

is that the infection not kill the cell

RNA TUMOR VIRUSES

RETROVIRUSES ONLY CANCER CAUSING RNA VIRUSES

PROTOTYPE RETROVIRUS: GAG (CORE PROTEINS) POL (REVERSE TRANSCRIPTASE) ENV (ENVELOPE PROTEINS)

MECHANISMS OF RETROVIRAL TRANSFORMATION

ACUTE TRANSFORMING RETROVIRUS CONTAINS ACTIVE ONCOGENE

SLOW TRANSFORMING RETROVIRUS INSERTIONAL MUTAGENESIS

DOES NOT CARRY AN ONCOGENE ITSELF

OTHER MECHANISMS (HTLV-I)

HTLV AND ADULT T-CELL LEUKEMIA

GEOGRAPHIC DISTRIBUTION ALL ATL PATIENTS ARE INFECTED VIRUS FOUND IN TUMOR CELLS VIRUS TRANSFORMS T CELLS IN

CULTURE

HTLV-1 and ATL

Proliferation

Malignancy

Kumar et al. Basic Pathology 6th ed. Figure 6-31

DNA TUMOR VIRUSES

EARLY GENES DNA REPLICATION / GENE EXPRESSION

LATE GENES CAPSID, PACKAGING TO PRODUCE

VIRAL PARTICLES

EARLY GENES = CANCER CAUSING

DNA VIRUS LIFE CYCLE

PRODUCTIVE CYCLE EARLY AND LATE GENES

CELL DEATH

NON-PRODUCTIVE CYCLE (LYSOGENIC) ONLY EARLY GENES

CELL SURVIVES MOST IMPORTANT FOR CARCINOGENESIS

DNA TUMOR VIRUSES ASSOCIATED WITH HUMAN CANCER

HUMAN PAPILLOMA VIRUS (HPV) AND CERVICAL CANCER

HEPATITIS B (HBV) AND LIVER CANCER (HEPATOMA)

EPSTEIN-BARR VIRUS (EBV) AND BURKITT’S LYMPHOMA

HPV AND CERVICAL CANCER EPIDEMIOLOGY CO-EXISTING INFECTIONS SPECIFIC TYPES (16, 18) HPV INTEGRATED DNA IN SOME

CELLS CAN TRANSFORM CELLS IN

CULTURE

THE “GRADUAL” DEVELOPMENT OF MALIGNANCY

CARCINOMA OF THE UTERINE CERVIX HPV INFECTION (KOILOCYTOSIS) CONDYLOMA DYSPLASIA (CIN) CARCINOMA IN SITU INVASIVE CARCINOMAUniversity

of Utah Web Site

Epstein-Barr Virus (EBV) Four cancers

Burkitt’s lymphoma B-cell lymphoma in immunosupressed Nasopharyngeal carcinoma Hodgkin’s disease

Mechanism LMP-1: cell growth and survival ( bcl-2) EBNA-2: activates cyclin D and src genes

Association with Burkitt’s High antibody titer DNA clonally present in tumor cells EBV transforms cultured lymphocytes

University of Kansas Web site

HBV AND HEPATOMA

GEOGRAPHIC DISTRIBUTION (EPIDEMIOLOGY)

CHRONIC INFECTION- RR 200X WOODCHUCKS (ANIMAL MODEL) INTEGRATED VIRAL DNA

Tumor Immunity General Principles

Tumors not entirely self Express non-self proteins

Immune-mediated recognition of tumor cells may be “positive mechanism of eliminating transformed cells

Immune surveillance

Tumor Antigens

Tumor Specific Antigens Present only on Tumor cells Recognized by cytotoxic T cells

Bound by class I MHC Several antigens in humans found that are

not unique for tumor, however are generally not expressed by normal tissue

Melanoma-associated antigen-1 (MAGE-1): Embryonal protein normally expressed in testis

Melanomas, breast ca, lung ca

Tumor Antigens Tumor Associated Antigens

Not unique to tumors, shared by normal cells

Differentiation- specific antigens CALLA (CD10) in early B cells Prostate specific antigen PSA

Antitumor Effector Mechanisms Cytotoxic T-cells

MHC restricted CD-8 cells (viruses) NK cells

Destroying tumor cells without prior sensitization

Macrophages Ifn-gamma

Humoral Mechanisms Via complement and NK cells

Antitumor Effector Mechanisms

Cytotoxic T-cell NK cell

MacrophageHumoralMechanisms

Kumar et al. Basic Pathology 6th ed. Figure 6-32

IMMUNOSURVAILLANCE Argument for:

Increased cancer in immunodeficient hosts 200x increase in immunodeficiencies (lymphoma)

X-linked lymphoproliferative disorder (XLP EBV related

Escape Mechanism Theories Selective outgrowth of antigen-negative

variants Loss or reduction of HLA (escape T-cells) Immunosuppression (Tumors secrete factors

TGF-b)

IMMUNOTHERAPY Replace suppressed components

of immune system or stimulate endogenous responses Adoptive Cellular Therapy

Incubation of lymphocytes with IL-2 to generate lymphokine activated killer (LAK) cells with potent antitumor activity

Enriched tumor specific cytotoxic T cells Tumor infiltrating lymphocytes (TIL)

Cytokine Therapy Activate specific and nonspecific

(inflammatory) host defenses. Interferon-a, TNF-a, Il-2, IFN-g

IFN-a activates NK cells, increase MHC expression on tumor cells

Used for hairy cell leukemia

Antibody-Based Therapy Antibodies as targeting agents for

delivery of cell toxins “magic bullet” Direct use of antibodies to activate

host immune system Her-2/neu in advance breast cancer