Medical Immunology Department of Immunology Yiwei Chu.

Medical ImmunologyDepartment of Immunology

Yiwei Chu

DEPARTMENT OF IMMUNOLOGY

Chapter 17

Immunity to tumors

June, 21, 2010


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


Cancer is a major health problem

worldwide and one of the most

important causes of morbidity and

mortality in children and adults.


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.


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.


Tumor Antigen


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.


Content







Tumor Antigen

The earliest classification:

Tumor-specific antigen

Tumor-associated antigen


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.


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


Tumor Antigen


Tumor Antigen

The modern classification is relies on

the molecular structure and source of

the antigen


Tumor Antigen


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


Content







Immune Responses to Tumors

T lymphocytes

Antibodies

NK cells

Macrophages



T lymphocytes

The killing of tumor cells by CD8+ CTL



T lymphocytes




T lymphocytes



Antibodies

The killing of tumor cells by activating

complement or by ADCC



Complement

System





NK cells

NK cells kill many types of tumor

cells,especially cells that have reduces

class I MHC expression and can escape

killing CTLs.


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.



NK cells



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.


Content







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



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.


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



Content







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


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


Immunotherapy

• Active immunotherapy

• Passive immunotherapy


Immunotherapy

Active immunotherapy

• Vaccination

• Augmentation of host immunity to

tumors with cytokines and

costimulators


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


Immunotherapy


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


Immunotherapy

Augmentation of host immunity to tumors


Immunotherapy

Passive immunotherapy

1.Adoptive Cellular Therapy

2.Anti-tumor Antibodies


Immunotherapy

Adoptive cellular therapy



Immunotherapy

Anti-tumor Antibodies

Her-2/Neu, CD20, CD10, CEA, CA-125, GD3

ganglioside


Key notes

Concepts: TSA, TAA

Evasion of immune responses by

tumors

Immunotherapy to tumors


Thank you!DEPARTMENT OF IMMUNOLOGY

Medical Immunology Department of Immunology Yiwei Chu.

Documents

tumor cells

tumorassociated antigens

tumor specific antigens

immunotherapy slide

growth of tumors

evasion of immune responses

immune system

individual tumors