Cancer and the Immune System Amar Bhatt Shirley Masand Jaime Warmkessel Immunology Chapter 22 April 22, 2003.

Cancer and theImmune System

Amar Bhatt

Shirley Masand

Jaime Warmkessel

ImmunologyChapter 22April 22, 2003

A Look Ahead

• Tumors and Metastasis

• Oncogenes and Cancer Induction

• Tumor Antigens

• Tumors and the Immune Response

• Immunotherapy

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Cancer and theImmune System

CancerCancer““altered self-cells that have escaped normal altered self-cells that have escaped normal growth regulation mechanisms”growth regulation mechanisms”

neoplasmneoplasm: tumor: tumor

benign vs. malignantbenign vs. malignant

metastasismetastasis: spreading of cancerous cells via : spreading of cancerous cells via blood or lymph to various tissuesblood or lymph to various tissues

MetastasisMetastasis22.1

Types of CancersTypes of Cancers

carcinomacarcinoma: endodermal/ectodermal tissue: endodermal/ectodermal tissue

leukemialeukemia//lymphomalymphoma: hematopoeitic stem cells: hematopoeitic stem cells

sarcomasarcoma: mesodermal connective tissues: mesodermal connective tissues

What makes cancer What makes cancer “cancer”?“cancer”?

1.1. decreased requirements for growth decreased requirements for growth factors and serumfactors and serum

2.2. are no longer anchorage dependentare no longer anchorage dependent

3.3. grow independently of densitygrow independently of density

normal cells:normal cells:

eventually enter Geventually enter Goo

confluent monolayerconfluent monolayer CHECKPOINT FAILURE CHECKPOINT FAILURE

contact inhibitioncontact inhibition

Malignant Malignant TransformationTransformation

are like are like in vitroin vitro cancers cancers two phasestwo phases

1.1. initiation (changes in genome)initiation (changes in genome)

2.2. promotion (proliferation)promotion (proliferation)

Malignant Malignant TransformationTransformation

chemical and physical carcinogenschemical and physical carcinogens

virally induced transformationvirally induced transformation

cultured tumors: good models for studycultured tumors: good models for study

cancer cells are basically immortalcancer cells are basically immortal

Oncogenes…Oncogenes…oncogeneoncogene: “cancer : “cancer

gene”; often found in gene”; often found in viral genomesviral genomes

proto-oncogeneproto-oncogene: : cellular counterpart cellular counterpart which can be turned which can be turned into an oncogeneinto an oncogene

What can go right?What can go right? induction of cellular induction of cellular

proliferationproliferation inhibition of cellular inhibition of cellular

proliferation, a.k.a. tumor-proliferation, a.k.a. tumor-suppressor genessuppressor genes

regulation of programmed regulation of programmed cell deathcell death

WhatWhat cancan gogo wrongwrong?? chromosomal translocationschromosomal translocations tandem repeats: HSRstandem repeats: HSRs mutations in proto-oncogenesmutations in proto-oncogenes viral integrationviral integration growth factors and their receptorsgrowth factors and their receptors

Induction of CancerInduction of Cancer

Fig. 22.2

Induction of CancerInduction of Cancer

Lets Visualize!Lets Visualize!

http://science.education.nih.gov/supplemhttp://science.education.nih.gov/supplements/nih1/cancer/activities/activity2_animents/nih1/cancer/activities/activity2_animations.htmations.htm

Tumors of the Immune SystemTumors of the Immune System

LymphomasLymphomas Solid tumors w/in lymphoid tissue (bone marrow, Solid tumors w/in lymphoid tissue (bone marrow,

lymph nodes, thymus)lymph nodes, thymus) Hodgkin’s & non-Hodgkin’sHodgkin’s & non-Hodgkin’s

http://www.lymphomainfo.net/http://www.lymphomainfo.net/

LeukemiasLeukemias Proliferate as single cellsProliferate as single cells Acute or Chronic depending on the progression of Acute or Chronic depending on the progression of

diseasedisease Acute- appear suddenly and progress rapidly; Acute- appear suddenly and progress rapidly;

arise is less mature cells (ie ALL, AML)arise is less mature cells (ie ALL, AML) Chronic- much less aggressive and develop Chronic- much less aggressive and develop

slowly; mature cells (ie CLL and CML)slowly; mature cells (ie CLL and CML)

Tumor AntigensTumor Antigens

TSTAs TSTAs Tumor Specific Transplantation AntigenTumor Specific Transplantation Antigen

TATAsTATAs Tumor Associated Transplantation AntigenTumor Associated Transplantation Antigen

TSTAsTSTAs

Unique to tumor cellsUnique to tumor cells DO NOTDO NOT occur on normal cells in the body occur on normal cells in the body Novel proteins created my mutation presented Novel proteins created my mutation presented

on class I MHCon class I MHC Can either be chemically/physically induced or Can either be chemically/physically induced or

virally induced tumor antigensvirally induced tumor antigens

Chemically/Physically InducedChemically/Physically Induced

Fig 22.7

•Specific Immunologic Response that canProtect against later challenge by live cellsOf the same line but not other tumor-lineCells. •Methylcholanthrene / UV light

Virally InducedVirally Induced

Express tumor antigens shared by all tumors induced Express tumor antigens shared by all tumors induced by the same virusby the same virus

Burkitt’s LymphomaBurkitt’s Lymphoma Epstein BarrEpstein Barr

HPVHPV

Fig 22.9

TATAsTATAs

NOT unique to tumor cellsNOT unique to tumor cells DO occur on normal cells in the bodyDO occur on normal cells in the body So where’s the problem?So where’s the problem?

Fetal/adult presenceFetal/adult presence Concentration of Growth Factors and Growth Concentration of Growth Factors and Growth

Factor ReceptorsFactor Receptors

TATAs cont’dTATAs cont’d

Oncofetal Tumor Antigens (AFP & CEA)Oncofetal Tumor Antigens (AFP & CEA) Normally appear in fetus before Normally appear in fetus before

immunocompetenceimmunocompetence Later recognized as non-selfLater recognized as non-self

Oncogene ProteinsOncogene Proteins Human MelanomasHuman Melanomas

Virally Induced TumorsVirally Induced Tumors

VirallyVirally induced tumors have the same induced tumors have the same antigens for each tumor caused by that antigens for each tumor caused by that virus. virus.

HPVHPV

Immune Response to Immune Response to TumorsTumors

Mostly a cell-mediated Mostly a cell-mediated responseresponse

NK CellsNK Cells Not MHC restrictedNot MHC restricted Fc receptor binds to antibody Fc receptor binds to antibody

coated tumor cell coated tumor cell ADCC ADCC Chedieak-Higashi syndromeChedieak-Higashi syndrome

MacrophagesMacrophages Not MHC restrictedNot MHC restricted Elicits ADCCElicits ADCC TNF-alphaTNF-alpha

Immune Surveillance TheoryImmune Surveillance Theory

So, you have a tumor cell.So, you have a tumor cell.Now what?Now what?

You need three things:You need three things:1.1. ““See” the cancerSee” the cancer

Ternary complex and costimulation by B7Ternary complex and costimulation by B7

2.2. Activate lymphocytesActivate lymphocytes Release IL-2, IFN-gamma, and TNF-alphaRelease IL-2, IFN-gamma, and TNF-alpha

3.3. Cancer cells must be susceptible to killingCancer cells must be susceptible to killing CTL lysis, macrophages, NK cellsCTL lysis, macrophages, NK cells

Info From:http://www.brown.edu/Courses/Bio_160/Projects1999/cancer/imevstca.html#Introduction

But if the body has all these defenses, why do

so many people still have cancer?

Conniving Cancer.Conniving Cancer.

Bad antibodies?Bad antibodies? Some antibodies do not protect against tumor Some antibodies do not protect against tumor

growth, but also growth, but also ENHANCEENHANCE it. it. Release of immunosuppressive cytokinesRelease of immunosuppressive cytokines

transforming growth factor-beta (TGF-beta), interleukin-10 transforming growth factor-beta (TGF-beta), interleukin-10 (IL-10) and vascular endothelial growth factor (VEGF) (IL-10) and vascular endothelial growth factor (VEGF)

Hide and go Seeking AntigenHide and go Seeking Antigen Antigens actually seem to “hide” in the presence of Antigens actually seem to “hide” in the presence of

antibodyantibody Also, some cancer cells completely shed Also, some cancer cells completely shed

themselves of the antigenthemselves of the antigen

Effect TGF-beta IL-10 VEGF

Inhibition of T-cell growth + - +

Inhibition of CTL differentiation + + +

Inhibition of cytokine production + + -

Induction of T-cell anergy + - -

Downregulation of cytotoxic potential + + -

Inhibition of antigen presentation + + -

Shift in the Th1-Th2 balance towards Th2

+ + -

Downregulation of adhesion/costimulatory molecules

+ + -

Resistance to CTL-mediated lysis - + -

Source: Chouaib et al 1997

Conniving Cancer cont.Conniving Cancer cont.

Reduction in Reduction in Class I MHC Class I MHC MoleculesMolecules

And the final blow…And the final blow…

Lack of Co- Lack of Co- Stimulatory Stimulatory SignalSignal

Cancer ImmunotherapyCancer Immunotherapy

Manipulation of Co-Stimulatory Manipulation of Co-Stimulatory SignalSignal

Enhancement of APC ActivityEnhancement of APC Activity Cytokine TherapyCytokine Therapy Monoclonal AntibodiesMonoclonal Antibodies Cancer VaccinesCancer Vaccines

Manipulation of Co-Manipulation of Co-Stimulatory SignalStimulatory Signal Tumor immunity can be enhanced by providing the Tumor immunity can be enhanced by providing the

co-stimulatory signal necessary for activation of CTL co-stimulatory signal necessary for activation of CTL precursors (CTL-Ps)precursors (CTL-Ps)

Fig. 22.11a Fig. 22.11a

Manipulation of Co-Manipulation of Co-Stimulatory Signal ContStimulatory Signal Cont..

Basis for VaccineBasis for Vaccine Prevent metastasis after surgical removal or Prevent metastasis after surgical removal or

primary melanoma in human patientsprimary melanoma in human patients

Enhancement of APC Enhancement of APC ActivityActivity GM-CSF (Granulocyte-macrophage colony-GM-CSF (Granulocyte-macrophage colony-

stimulating factor)stimulating factor)remember:remember: CSFs are cytokines that induce the CSFs are cytokines that induce the

formation of distinct hematopoietic cell linesformation of distinct hematopoietic cell lines

Fig 22.11bFig 22.11b

Cytokine TherapyCytokine Therapy

Use of recombinant cytokines (singly or Use of recombinant cytokines (singly or in combination) to augment an immune in combination) to augment an immune response against cancerresponse against cancer Via isolation and cloning of various cytokine Via isolation and cloning of various cytokine

genes such as:genes such as: IFN-IFN-αα, , ββ, and , and γγ Interleukin 1, 2, 4, 5, and 12Interleukin 1, 2, 4, 5, and 12 GM-CSF and Tumor necrosis factor (TNF)GM-CSF and Tumor necrosis factor (TNF)

Cytokine Therapy Cont.Cytokine Therapy Cont.I. I. InterferonsInterferons

• • Most clinical trials involve IFN-Most clinical trials involve IFN-αα• • Has been shown to induce tumor regression in Has been shown to induce tumor regression in

hematologic malignancies i.e. leukemias, hematologic malignancies i.e. leukemias, lymphomas, melanomas and breast cancerlymphomas, melanomas and breast cancer

• • All types of IFN increase MHC I expression All types of IFN increase MHC I expression • • IFN-IFN-γγ also has also been shown to increase also has also been shown to increase MHC MHC

II expressionon macrophages and increase II expressionon macrophages and increase activity of Tc cells, macrophages, and activity of Tc cells, macrophages, and

NKsNKs

Cytokine Therapy Cont.Cytokine Therapy Cont.

II.II. Tumor Necrosis FactorsTumor Necrosis Factors• • Kills some tumor cells Kills some tumor cells

• • Reduces proliferation of tumor cells without Reduces proliferation of tumor cells without

affecting normal cells affecting normal cells

How?How?

• • Hemorrhagic necrosis and regression, inhibitsHemorrhagic necrosis and regression, inhibits

tumor induced vascularization (angio-tumor induced vascularization (angio-genesis)genesis)

by damaging vascular endothelium by damaging vascular endothelium

Cytokine Therapy Cont.Cytokine Therapy Cont. III.III. In Vitro-Activited LAK & TIL cells In Vitro-Activited LAK & TIL cells

A. Lymphocytes are activated against tumor A. Lymphocytes are activated against tumor

antigens in vitroantigens in vitro • • Cultured with x-irradiated tumor Cultured with x-irradiated tumor

cells in cells in presence of IL-2presence of IL-2 • • Generated Generated lymphokine activated lymphokine activated killer killer

cellscells (LAKs), which kill tumor (LAKs), which kill tumor cells cells

without affecting normal cellswithout affecting normal cells

In Vitro-Activated LAK and TIF cells In Vitro-Activated LAK and TIF cells Cont.Cont.

B. Tumors contain lymphocytes that have B. Tumors contain lymphocytes that have

infiltrated tumor and act in anti-tumor infiltrated tumor and act in anti-tumor

responseresponse

• • via biopsy, obtained cells and via biopsy, obtained cells and

expanded population in vitro with expanded population in vitro with

• • generated generated tumor-infiltrating tumor-infiltrating lympho-lympho-

cytescytes (TILs) (TILs)

Monoclonal AntibodiesMonoclonal Antibodies

• • Anti-idiotype Anti-idiotype

• • Growth FactorsGrowth Factors

-HER2-HER2

• • ImmunotoxinsImmunotoxins

Cancer VaccinesCancer Vaccines

• • GeneticGenetic

BiochemicalBiochemical

HPVHPV

Human Papilloma VirusHuman Papilloma Virus E6E6 E7E7

From Normal to Abnormal:

For more infoFor more info

HPVHPV Cancer VaccinesCancer Vaccines

This Day Has This Day Has Been Brought to Been Brought to you By the you By the Letter…Letter…

CCC is for Cancer!C is for Cancer!