Transcript 幻灯片 1 - Shandong University
Chapter 20 Tumor Immunology
Contents Introduction PartⅠ Tumor antigens PartⅡ Immune response to tumors Part Ⅲ Mechanism of tumor escape from immune surveillance PartⅣ Immunotherapy of tumors
Introduction
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
Tumor rejection antigens are specific to individual tumors
Part
Ⅰ
Tumor antigens
Tumor antigens : Refer to all newly expressed antigens or over expressed antigens during the generation and development of the tumor.
Ⅰ
.Classification of tumor antigens
Base on their patterns of expression:
Tumor specific antigen (TSA)
Tumor associated antigens (TAA)
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
methyl-cholanthrene,MCA
Conclusion from this experiment
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.
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
3.
4.
Tumor antigens induced by virus es
proteins coded by Mutated oncogene or suppressor oncogene
TATAS expressed on human melanoma cells
1. embryonic antigens
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) Carcinoembryonic antigen (CEA)
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.
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
(2) alpha-fetoprotein (AFP)
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.
Alpha fetoprotein: concentrations Normal concentration: <20 ng/ml Abnormal concentrations 100-350 possible hepatoma 350-500 probable hepatoma 500-100 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
Humoral immunity Macrophages Dendritic cells
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-classⅠMHC 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 Ⅰmolecule. First line of defence of immune surveillance
activated Tumor cell
3. Macrophages(M Φ)
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 NK NKT γδT DC IFNγ Innate IR recognises tumour cell establishment NK NKT γδ T NK NK CXC10-12 IFNγ DC LN NK cells and other effectors recruited to site by chemokines, which also target tumour growth directly .
NK NKT IFNγ CXC10-12 CTL CD4 CTL CTL CD4 CTL MΦ MΦ MΦ Tumour-specific T cells home to tumour site, along with macrophages and other effectors to eliminate tumour cells.
Ⅱ
. Humoral immune responses
Antibodies: ① Activating complement ② ADCC ③ Opsonization
Antitumor Effector Mechanisms
CTL Humoral Mechanisms
Tumor cell
NK cell Macrophage
Kumar et al. Basic Pathology 6 th ed. Figure 6-32
Part
Ⅲ
Mechanism of Tumor Immune Escape
Factors related to tumor cells Factors related to the host’s immune system
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
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