Chapter 20 Tumor Immunology

Introduction Part Ⅰ Tumor antigens Part Ⅱ Immune response to tumors Part Ⅲ Mechanism of tumor escape from immune surveillance Part Ⅳ Immunotherapy of tumors ContentsContents

Tumor 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 Introduction

Tumor rejection antigens are specific to individual tumors

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

Base on their patterns of expression: Tumor specific antigen (TSA) Tumor associated antigens (TAA) Ⅰ.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-ray Tumor low-specific antigens TSA---expressed on more than one kind of tumor, induced by virus

Discovery of tumor specific transplantation antigens, TSTA Discovery of tumor specific transplantation antigens, TSTA methyl-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,TAA Antigens that are also expressed on normal cells, but high expressed on tumor cells. Without tumor specificity: CEA, AFP

Ⅱ.Common human tumor antigens 1. Embryonic antigens Embryonic antigens 2. Tumor antigens induced by viruses Tumor antigens induced by virus 3. proteins coded by Mutated oncogene or suppressor oncogeneMutated oncogene or suppressor oncogene 4. TATAS 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

High CEA level is normally restricted to cells of the gut, pancreas, and liver in the course of 2-6 months of gestation, and low level is found in serum of normal adult(<5  g/ml). CEA level of serum is increased in many carcinomas,such as the colon, pancreas, stomach, and breast. The level of serum CEA is used to monitor the persistence or recurrence of the tumors after treatment. (1) (1) Carcinoembryonic antigen (CEA)

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 use  Adjunct in diagnosis  Staging and prognosis  Monitoring response to therapy  Detection 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: concentrations  Normal concentration: <20 ng/ml  Abnormal concentrations  possible hepatoma  probable hepatoma  likely hepatoma  >1000 HEPATOMA

2. Tumor antigens induced by viruses: HBV liver cancer HPV cervical carcinoma EBV 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 Ⅱ Mechanism of Immune Response T cells: αβT, γδT NK cells Cellular immunity Macrophages Dendritic cells Humoral immunity

Ⅰ.Cell-mediated Immune Response T cells NK cells Macrophages(MΦ) 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 （ CTL ） CD4+Th cells

(2)  T cells Non-class Ⅰ MHC restriction Its target cells are not hypersensitive to NK cells First line of defence of immune surveillance

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

Tumor cell activated

3. Macrophages(MΦ) ① APC ② release of lysosomal enzymes, reactive oxygen intermediates, nitric oxide ③ ADCC ④ secrete cytokines 4. Dendritic cells: ① APC------Induce adaptive immune response ② Inhibit tumor growth directly

IR-Mediated Tumour Elimination γδ T NKT NK IFNγ NK DC LN CXC10-12 NK cells and other effectors recruited to site by chemokines, which also target tumour growth directly. γδT NKT NK DC IFNγ Innate IR recognises tumour cell establishment CTL NKT NK MΦMΦ IFNγ CTL CD4 CXC10-12 CTL CD4 MΦMΦ MΦMΦ Tumour-specific T cells home to tumour site, along with macrophages and other effectors to eliminate tumour cells.

Antibodies: ① Activating complement ② ADCC ③ Opsonization Ⅱ. Humoral immune responses

Antitumor Effector Mechanisms CTL NK cell Macrophage Humoral Mechanisms Humoral Mechanisms Kumar et al. Basic Pathology 6 th ed. Figure 6-32 Tumor cell

Factors related to tumor cells Factors related to the host’s immune system Part Ⅲ Mechanism of Tumor Immune Escape

Ⅰ. Factors related to tumor cells 1.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 immunosurveillance Lack of Neo-antigens

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

2. covering or blocking of tumor antigens on the surface of the tumor cells 3. Diminution or absence of MHC class I molecule 4. Lack of co-stimulatory molecule on the surface of tumor cells 5. Immune inhibitors secreted by tumor cells

Escape from immunosurveillance

Ⅱ.Factors related to host’s immune system 1. Immunodeficiency 2. Suppressing immune function by tumor directly or indirectly

Active immunotherapy Target immunotherapy Adoptive immunotherapy Cytokine therapy Gene therapy Part Ⅴ Immunotherapy of tumors

Stimulation of active host immune responses to tumors: Vaccination with tumor cells and tumor antigens, or with APC. Augmentation of host immunity to tumors with cytokines and costimulators Nonspecific 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 with T 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-γworks 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