Medical Immunology

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Medical Immunology

• Department of Immunology

Yiwei Chu
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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 Her-2/neu (breast and other carcinomas)
Products of oncogenes, tumor suppressor genes 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)
Products of oncogenic viruses EBNA-1 protein of EBV (EBV-associated lymphomas, nasopharyngeal carcinoma)
Products of oncogenic viruses SV40 T antigen (SV40-induced rodent tumors)
Oncofetal antigens Carcinoembryonic antigen (CEA) on many tumors, also expressed in liver and other tissues during inflammation
Oncofetal antigens Alpha-fetoprotein (AFP)
Glycolipids and glycoproteins GM2 GD2 on melanomas
Differentiation antigens normally present in tissue of origin Prostate-specific antigen
Differentiation antigens normally present in tissue of origin 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, 2991057-1061 Jun Shimizu et al
Nat. Immunology. 2002,3(2) 135-142 Shevach. EM
Nat Rev. Immunol. 2002, 2389-400
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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
CD4CD25TregNegative regulator

• Existing a large amount of CD4CD25Tregs in TILs
• Regrssion the tumorigenesis if deleting the
  CD4CD25Treg

Tyler J. Curiel et al Nature Medicine. 2004,
10(9)942-949 Zhang,L et al N. Engl. J. Med.
2003, 348201-213
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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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27 years later. Resolution
Immunotherapy

• 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
• Killed tumor vaccine
• Purified tumor antigens
• Professional APC-based vaccines
• Cytokine- and costimulator-enhanced vaccines
• DNA vaccines
• 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
Tumor Idiotype Protein As tumor specific- antigen
Immunization with Antigen-pulsed DCs
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
• Adoptive Cellular Therapy
• 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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DEPARTMENT OF IMMUNOLOGY
Thank you!