Transcript Immune Responses to Tumors

Medical Immunology
Department of Immunology
Yiwei Chu
Chapter 17
Immunity to tumors
June, 21, 2010
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Content
1. General Features
2. Tumor antigen
3. Immune Responses
4. Evasion of Immune Responses
5. Immunotherapy
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Cancer is a major health problem
worldwide and one of the most
important causes of morbidity and
mortality in children and adults.
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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 of
the corporation known as The Walt Disney
Company died at the age of 65 from lung cancer,
making him one of the most famous celebrities
to 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 away
on September 26, 2008,at the age of 83.
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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.
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Tumor Antigen
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 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.
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Content
1. General Features
2. Tumor antigen
3. Immune Responses
4. Evasion of Immune Responses
5. Immunotherapy
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Tumor Antigen
The earliest classification:
 Tumor-specific antigen
 Tumor-associated antigen
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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.
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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
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Tumor Antigen
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Tumor Antigen
The modern classification is relies on
the molecular structure and source of
the antigen
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Tumor Antigen
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Tumor Antigen
Type of antigen
Examples of human tumor antigens
Products of oncogenes,
tumor suppressor genes
Oncogenes: Ras mutations (∼10% of human carcinomas), p210
product of Bcr/Abl rearrangements (CML), overexpressed Her2/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
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Content
1. General Features
2. Tumor antigen
3. Immune Responses
4. Evasion of Immune Responses
5. Immunotherapy
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Immune Responses to Tumors
T lymphocytes
Antibodies
NK cells
Macrophages
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Immune Responses to Tumors
T lymphocytes
The killing of tumor cells by CD8+ CTL
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Immune Responses to Tumors
T lymphocytes
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Immune Responses to Tumors
T lymphocytes
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Immune Responses to Tumors
Antibodies
The killing of tumor cells by activating
complement or by ADCC
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Immune Responses to Tumors
Complement
System
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Immune Responses to Tumors
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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.
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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.
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Immune Responses to Tumors
NK cells
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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.
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Content
1. General Features
2. Tumor antigen
3. Immune Responses
4. Evasion of Immune Responses
5. Immunotherapy
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Evasion of Immune Responses
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):771-782
Hori S: Science,2003, 299:1057-1061
Jun Shimizu et al: Nat. Immunology. 2002,3(2): 135-142
Shevach. EM: Nat Rev. Immunol. 2002, 2:389-400
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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.
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Evasion of Immune Responses
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
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Content
1. General Features
2. Tumor antigen
3. Immune Responses
4. Evasion of Immune Responses
5. Immunotherapy
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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
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Immunotherapy
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
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Immunotherapy
• Active immunotherapy
• Passive immunotherapy
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Immunotherapy
Active immunotherapy
• Vaccination
• Augmentation of host immunity to
tumors with cytokines and
costimulators
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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
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Immunotherapy
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Immunotherapy
Dendritic Cell- Based Vaccines
Myeloma cell
Tumor Biopsy
+
Vaccine Production
Fusion
+
Leukapheresis
Dendritic Cells
Immunization with
Antigen-pulsed DCs
Tumor Idiotype Protein
As tumor specificantigen
Co-culture
Regression of Lymphoma following vaccination with Id-pulsed DC
Levy R, Englman E, et al. Blood 2002, 90: 1517-1526
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Immunotherapy
Augmentation of host immunity to tumors
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Immunotherapy
Passive immunotherapy
1.Adoptive Cellular Therapy
2.Anti-tumor Antibodies
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Immunotherapy
Adoptive cellular therapy
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Immunotherapy
Anti-tumor Antibodies
Her-2/Neu, CD20, CD10, CEA, CA-125, GD3
ganglioside
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Key notes

Concepts: TSA, TAA

Evasion of immune responses by
tumors

Immunotherapy to tumors
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Thank you!
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