Chapter 20 Tumor Immunology. Introduction Part Ⅰ Tumor antigens Part Ⅱ Immune response to tumors Part Ⅲ Mechanism of tumor escape from immune surveillance.

Chapter 20

Tumor Immunology

IntroductionPart Tumor antigensPart Immune response to tumorsPart Mechanism of tumor escape from immune surveillancePart Immunotherapy of tumorsContents

IntroductionTumor immunology is mainly to study the immunogenicity of tumor and the mechanism of immune response to tumor, to demonstrate the relationship between the status of immune system and the generation, development of tumor, to explore the method of tumor diagnosis, therapy and prevention.Immunosurveillance

Tumor rejection antigens are specific to individual tumors

Part Tumor antigensTumor antigens: Refer to all newly expressed antigens or over expressed antigens during the generation and development of the tumor.

Base on their patterns of expression:

Tumor specific antigen (TSA)Tumor associated antigens (TAA) .Classification of tumor antigens

1.Tumor-specific antigens (TSA)TSA: Antigens that are only expressed on tumor cells but not on normal cells. high specificity. Tumor high-specific antigens TSA---only expressed on one kind of tumor, induced by physiochemical factors, such as X-rayTumor low-specific antigens TSA---expressed on more than one kind of tumor, induced by virus

Discovery of tumor specific transplantation antigens, TSTAmethyl-cholanthrene,MCA

Tumors express antigens that are recognized as foreign by the immune system of the tumor-bearing host.

Immune response frequently fail to prevent the growth of tumors.

The immune system can be activated by external stimulator to effectively kill tumor cells and eradicate tumors.Conclusion from this experiment

2.Tumor-associated antigens,TAAAntigens that are also expressed on normal cells, but high expressed on tumor cells. Without tumor specificity: CEA, AFP

.Common human tumor antigensEmbryonic antigensTumor antigens induced by virusesproteins coded by Mutated oncogene or suppressor oncogeneTATAS expressed on human melanoma cells

embryonic antigens are proteins that are express at high levels on cancer cells and in normal developing fetal, but peter out or very low level in adult.Their main function is that they provide markers that aid diagnosis of tumor. Carcinoembryonic antigen (CEA) alpha-fetoprotein (AFP)1. embryonic antigens

CEA levels in normal individuals are below 2.5 ng/ml, but it increases significantly in certain malignancies, particularly colo-rectal cancers. It may also rise in some nonmalignant conditions (e.g., chronic cirrhosis, pulmonary emphysema, heavy smoking). Levels 4-5-fold of normal have been used to predict recurrence of colo-rectal tumors.

Carcinoembryonic antigen:clinical useAdjunct in diagnosisStaging and prognosisMonitoring response to therapyDetection of tumor recurrence

Carcinoembryonic antigen:clinical use

AFP is a circulating glycoprotein normally synthesized and secreted by the yolk sac and liver of fetal.Serum levels of AFP is very low in serum of adult (20ng/ml), and the concentration of AFP is up to 500ng/ml in serum of patients with hepatocellular carcinoma. higher rise in this protein is used for monitoring hepatomas and testicular cancers. AFP level may also be raised in some nonmalignant conditions, such as cirrhosis, hepatitis and other forms of liver damage.(2) alpha-fetoprotein (AFP)

Alpha fetoprotein: concentrationsNormal concentration: 1000 HEPATOMA

2. Tumor antigens induced by viruses:HBV------ liver cancer HPV------ cervical carcinomaEBV------ B cell lymphoma and nasopharyngeal carcinoma

3. Products of mutated genes:Some tumor antigens are produced by mutated genes, such as suppressor oncogenes p53 and pro-oncogene ras

Some patients with cancer have circulating CD4+ and CD8+T cells that can respond to the products of mutated genes such as Ras and P53.Furthermore, in animals, immunization with mutated Ras or P53 proteins induces CTLs and rejection responses against tumors expressing these mutants.

Overexpressed cellular proteins and abnormally expressed proteins:gp100, MAGE in melanomas Cancer-testis antigens

Part Mechanism of Immune Response T cells: T, T NK cellsCellular immunity Macrophages Dendritic cellsHumoral immunity

.Cell-mediated Immune ResponseT cellsNK cells Macrophages(M) Dendritic cells (DCs)

1. T lymphocytes:(1) T cells The principal mechanism of tumor immunity is killing of tumor cells by CTL Tumor antigens

DC cross presentation CD8+T CTLCD4+Th cells

(2) T cellsNon-classMHC restrictionIts target cells are not hypersensitive to NK cellsFirst line of defence of immune surveillance

2. NK cells:NK cells are broad-spectrum killer cellsIt can kill target cells with low level or non MHC class molecule. First line of defence of immune surveillance

Tumor cellactivated

3. Macrophages(M) APC release of lysosomal enzymes, reactive oxygen intermediates, nitric oxide ADCC secrete cytokines

4. Dendritic cells: APC------Induce adaptive immune response Inhibit tumor growth directly

IR-Mediated Tumour Elimination

Antibodies: Activating complement ADCC Opsonization. Humoral immune responses

Antitumor Effector MechanismsCTLNK cellMacrophageHumoralMechanismsKumar et al. Basic Pathology 6th ed. Figure 6-32Tumor cell

Part Mechanism of Tumor Immune Escape Factors related to tumor cells

Factors related to the hosts immune system

. Factors related to tumor cells1.low immunogenicity of tumor antigens and antigenic modulation (1) low immunogenicity of tumor antigens The failure of immunosurveillance may be the fact that in the early development of a tumor, the amount of antigen may be too small to stimulate the immune system.

Escape from immunosurveillanceLack of Neo-antigens

(2) antigenic modulation: is a phenomenon that cell-surface tumor antigens are decrease or lose because of attack of hosts humoral immune.

2. covering or blocking of tumor antigens on the surface of the tumor cells3. Diminution or absence of MHC class I molecule4. Lack of co-stimulatory molecule on the surface of tumor cells5. Immune inhibitors secreted by tumor cells

Escape from immunosurveillance

.Factors related to hosts immune system1. Immunodeficiency

2. Suppressing immune function by tumor directly or indirectly

Active immunotherapyTarget immunotherapyAdoptive immunotherapyCytokine therapyGene therapyPart Immunotherapy of tumors

Stimulation of active host immuneresponses to tumors:Vaccination with tumor cells and tumor antigens, or with APC.Augmentation of host immunity to tumors with cytokines and costimulatorsNonspecific stimulation of the immune system

Vaccination with tumor cells and tumor antigens

DC:Use primed dendritic cells APCs can be fed tumor antigens in the laboratory and then injected into a patient. The injected cells are primed to activate T cells Alternatively, DCs can be infected with a viral vector that contains the gene for a tumor antigen.

Use of tumor specific/associated antigens monoclonal antibodies

Adoptive immunotherapy Adoptive cellular immunotherapy is the transfer of cultured immune cells that have anti-tumor reactivity into a tumor-bearing host. LAK, TIL, CD3AK, CTL

Passive immunotherapy for tumors withT cells and antibodies:Therapy with anti-tumor antibodies: Monoclonal antibodies conjugated drugs Adoptive cellular therapy: LAK,TIL,CD3AK,CTL

Cytokines may also be administered systemically for the treatment of human tumors.IL-2 works by stimulating the proliferation and anti-tumor activity of NK cells and CTLs.IFN-works by increasing the cytolytic activity of NK cells and class I MHC expression on various cell types.Their side effects limited this treatment.

Augmentation of host immunity to tumors with cytokines and costimulators

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