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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!