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Medical ImmunologyDepartment of Immunology
Yiwei Chu
DEPARTMENT OF IMMUNOLOGY
Chapter 17
Immunity to tumors
June, 21, 2010
DEPARTMENT OF IMMUNOLOGY
Content
1. General Features 1. General Features
2. Tumor antigen2. Tumor antigen
3. Immune Responses3. Immune Responses
4. Evasion of Immune Responses4. Evasion of Immune Responses
5. Immunotherapy5. Immunotherapy
DEPARTMENT OF IMMUNOLOGY
Cancer is a major health problem
worldwide and one of the most
important causes of morbidity and
mortality in children and adults.
DEPARTMENT OF IMMUNOLOGY
Robin Bush
The sister of George W. Bush, die from leukemia,at the age of 4.
Walt Disney
This famous animator, producer and co-founder ofthe corporation known as The Walt Disney Company died at the age of 65 from lung cancer,making him one of the most famous celebritiesto have died from smoking.
Paul Newman
Paul Newman was of course a great actor,but was known well for his healthy line of food.He struggled with lung cancer, and passed awayon September 26, 2008,at the age of 83.
DEPARTMENT OF IMMUNOLOGY
General Features
Tumor express antigens that are recognized as
foreign by the immune system of the tumor-bearing
host.
Immune responses frequently fail to prevent the
growth of tumors.
The immune system can be activated external
stimuli to effectively kill tumor cells and eradicate
tumors.
DEPARTMENT OF IMMUNOLOGY
Tumor Antigen
DEPARTMENT OF IMMUNOLOGY
Immune responses frequently fail to prevent the growth of tumors
First, tumor cells are derived from host cells.
Second, the rapid growth and spread of tumors
Third, specialized mechanisms for evading host
immune responses.
DEPARTMENT OF IMMUNOLOGY
Content
1. General Features 1. General Features
2. Tumor antigen2. Tumor antigen
3. Immune Responses3. Immune Responses
4. Evasion of Immune Responses4. Evasion of Immune Responses
5. Immunotherapy5. Immunotherapy
DEPARTMENT OF IMMUNOLOGY
Tumor Antigen
The earliest classification:
Tumor-specific antigen
Tumor-associated antigen
DEPARTMENT OF IMMUNOLOGY
Tumor Antigen
Tumor-specific antigen
Antigen that are expressed on tumor cells but
not on normal cells were called tumor- specific
antigens; some of these antigens are unique
to individual tumors, whereas others are
shared among tumors of the same type.
DEPARTMENT OF IMMUNOLOGY
Tumor Antigen
Tumor-associated antigen
Tumor antigens that are also expressed on
normal cells were called tumor-associated
antigens; in most cases, these antigens are
normal cellular constituents whose expression
is aberrant or dysregulated in tumors
DEPARTMENT OF IMMUNOLOGY
Tumor Antigen
DEPARTMENT OF IMMUNOLOGY
Tumor Antigen
The modern classification is relies on
the molecular structure and source of
the antigen
DEPARTMENT OF IMMUNOLOGY
Tumor Antigen
DEPARTMENT OF IMMUNOLOGY
Tumor Antigen Type of antigen Examples of human tumor antigensProducts of oncogenes, tumor suppressor genes
Oncogenes: Ras mutations (∼10% of human carcinomas), p210 product of Bcr/Abl rearrangements (CML), overexpressed Her-2/neu (breast and other carcinomas)
Tumor supressor genes: mutated p53 (present in ∼50% of human tumors)
Mutants of cellular genes not involved in tumorigenesis
p91A mutation in mutagenized murine mastocytoma; various mutated proteins in melanomas recognized by CTLs
Products of genes that are silent in most normal tissues
Cancer/testis antigens expressed in melanomas and many carcinomas; normally expressed mainly in the testis and placenta
Products of overexpressed genes
Tyrosinase, gp100, MART in melanomas (normally expressed in melanocytes)
Products of oncogenic viruses
Papillomavirus E6 and E7 proteins (cervical carcinomas)
EBNA-1 protein of EBV (EBV-associated lymphomas, nasopharyngeal carcinoma)
SV40 T antigen (SV40-induced rodent tumors)
Oncofetal antigens Carcinoembryonic antigen (CEA) on many tumors, also expressed in liver and other tissues during inflammation
Alpha-fetoprotein (AFP)
Glycolipids and glycoproteins GM2 GD2 on melanomas
Differentiation antigens normally present in tissue of origin
Prostate-specific antigen
Markers of lymphocytes: CD10, CD20, Ig idiotypes on B cells
DEPARTMENT OF IMMUNOLOGY
Content
1. General Features 1. General Features
2. Tumor antigen2. Tumor antigen
3. Immune Responses3. Immune Responses
4. Evasion of Immune Responses4. Evasion of Immune Responses
5. Immunotherapy5. Immunotherapy
DEPARTMENT OF IMMUNOLOGY
Immune Responses to Tumors
T lymphocytes
Antibodies
NK cells
Macrophages
DEPARTMENT OF IMMUNOLOGY
Immune Responses to Tumors
T lymphocytes
The killing of tumor cells by CD8+ CTL
DEPARTMENT OF IMMUNOLOGY
Immune Responses to Tumors
T lymphocytes
DEPARTMENT OF IMMUNOLOGY
DEPARTMENT OF IMMUNOLOGY
Immune Responses to Tumors
T lymphocytes
DEPARTMENT OF IMMUNOLOGY
Immune Responses to Tumors
Antibodies
The killing of tumor cells by activating
complement or by ADCC
DEPARTMENT OF IMMUNOLOGY
Immune Responses to Tumors
Complement
System
DEPARTMENT OF IMMUNOLOGY
Immune Responses to Tumors
DEPARTMENT OF IMMUNOLOGY
Immune Responses to Tumors
NK cells
NK cells kill many types of tumor
cells,especially cells that have reduces
class I MHC expression and can escape
killing CTLs.
DEPARTMENT OF IMMUNOLOGY
engagement of inhibitory NK cell receptors such as KIR and CD94/NKG2 by class I MHC molecules delivers an inhibitory signal that counteracts the activation signal.
DEPARTMENT OF IMMUNOLOGY
Immune Responses to Tumors
NK cells
DEPARTMENT OF IMMUNOLOGY
Immune Responses to Tumors
Macrophages
Dual role of macrophages in tumor growth and angiogenesis:
They activate and present tumor antigens to T cells, which are then activated to kill tumor cells.
However, tumor cells are often capable of escaping the immune machinery. As the immune surveillance is not sufficient anymore, tumor-associated macrophages contribute to tumor progression.
DEPARTMENT OF IMMUNOLOGY
Content
1. General Features 1. General Features
2. Tumor antigen2. Tumor antigen
3. Immune Responses3. Immune Responses
4. Evasion of Immune Responses4. Evasion of Immune Responses
5. Immunotherapy5. Immunotherapy
DEPARTMENT OF IMMUNOLOGY
The key of tumor growth, migration and metastasis is that tumor
cells evade immune destruction, often called tumor escape.
Turk MJ, J.Exp.Med. 2004, 200(6):771-782Hori S: Science,2003, 299:1057-1061Jun Shimizu et al: Nat. Immunology. 2002,3(2): 135-142Shevach. EM: Nat Rev. Immunol. 2002, 2:389-400
Evasion of Immune Responses
DEPARTMENT OF IMMUNOLOGY
Evasion of Immune Responses
Class I MHC expression may be down-regulated on tumor cells so that they cannot be recognized by CTLs.
Tumor lose expression of antigen that elicit immune responses.
Tumors may fail to induce CTLs because most tumor cells do not express costimulators or class II MHC molecules.
The products of tumor cells may suppress antitumor immune responses.
Tumor antigens may induces may induce specific immunologic tolerance.
DEPARTMENT OF IMMUNOLOGY
CD4+CD25+Treg : Negative regulator
Existing a large amount of
CD4+CD25+Tregs in TILs
Regrssion the tumorigenesis
if deleting the CD4+CD25+Treg
Tyler J. Curiel et al: Nature Medicine. 2004, 10(9):942-949 Zhang,L et al: N. Engl. J. Med. 2003, 348:201-213
Evasion of Immune Responses
DEPARTMENT OF IMMUNOLOGY
Content
1. General Features 1. General Features
2. Tumor antigen2. Tumor antigen
3. Immune Responses3. Immune Responses
4. Evasion of Immune Responses4. Evasion of Immune Responses
5. Immunotherapy5. Immunotherapy
DEPARTMENT OF IMMUNOLOGY
Immunotherapy
History Cancer Immunosurveillance Hypothesis (Controversy to Resolution) ‘Inheritable genetic changes must be common in somatic cells and a proportion of these change will represent a step
toward malignancy. It is an evolutionary necessity that there should be some mechanism for eliminating or inactivating such potentially dangerous mutant cells and it is postulated that this mechanism is of immunological character’
----- Sir MacFarlane Burnet, 1964
Fundamental Prediction: Immunodeficient individuals should show a significant increase in tumor incidence. However, ‘Athymic-nude mice and normal mice showed no differences in either latent period or incidence of local sarcomas or lung
adenomas within 120 days after administration of 3-methylcholanthrene at birth’ ----- Stutman O, et al. Science 183(4124): 534. 1974
DEPARTMENT OF IMMUNOLOGY
27 years later…. Resolution
Increased Incidence of MAC-Induced Tumor Detected In Mice With Well-Defined Genetic Immunodeficiencies. Shankaran et al. Nature 410: 1107-1111 2001
An accumulation of immune cells at tumor sites correlates with improved prognosis. Zhang et al. N Engl J Med 348: 203-213 2003
First human melanoma tumor antigen (MAGE-1) was identified. T Boon et al. Science, Vol 254, Issue 5038, 1643-1647 1991
Immunotherapy
DEPARTMENT OF IMMUNOLOGY
Immunotherapy
• Active immunotherapy
• Passive immunotherapy
DEPARTMENT OF IMMUNOLOGY
Immunotherapy
Active immunotherapy
• Vaccination
• Augmentation of host immunity to
tumors with cytokines and
costimulators
DEPARTMENT OF IMMUNOLOGY
Immunotherapy
Active immunotherapy------Vaccination
1. Killed tumor vaccine
2. Purified tumor antigens
3. Professional APC-based vaccines
4. Cytokine- and costimulator-enhanced vaccines
5. DNA vaccines
6. Viral vectors
DEPARTMENT OF IMMUNOLOGY
Immunotherapy
DEPARTMENT OF IMMUNOLOGY
Tumor BiopsyVaccine Production
Leukapheresis
Dendritic Cells
Co-culture
+
Fusion
Myeloma cell
Tumor Idiotype ProteinAs tumor specific- antigen
+
Immunization withAntigen-pulsed DCs
Dendritic Cell- Based Vaccines
Regression of Lymphoma following vaccination with Id-pulsed DCLevy R, Englman E, et al. Blood 2002, 90: 1517-1526
Immunotherapy
DEPARTMENT OF IMMUNOLOGY
Immunotherapy
Augmentation of host immunity to tumors
DEPARTMENT OF IMMUNOLOGY
Immunotherapy
Passive immunotherapy
1.Adoptive Cellular Therapy
2.Anti-tumor Antibodies
DEPARTMENT OF IMMUNOLOGY
Immunotherapy
Adoptive cellular therapy
DEPARTMENT OF IMMUNOLOGY
DEPARTMENT OF IMMUNOLOGY
Immunotherapy
Anti-tumor Antibodies
Her-2/Neu, CD20, CD10, CEA, CA-125, GD3
ganglioside
DEPARTMENT OF IMMUNOLOGY
Key notes
Concepts: TSA, TAA
Evasion of immune responses by
tumors
Immunotherapy to tumors
DEPARTMENT OF IMMUNOLOGY
Thank you!DEPARTMENT OF IMMUNOLOGY