Cancer Immunology Introduction Ags expressed by cancer cells
-
Upload
many87 -
Category
Health & Medicine
-
view
4.716 -
download
0
Transcript of Cancer Immunology Introduction Ags expressed by cancer cells
Cancer ImmunologyCancer Immunology
IntroductionIntroduction Ags expressed by cancer cellsAgs expressed by cancer cells Nature of immune responseNature of immune response How cancer evades immune How cancer evades immune
systemsystem ImmunotherapyImmunotherapy
Cancer Introduction
Cancer Introduction
Uncontrolled growth produces a tumor or Uncontrolled growth produces a tumor or neoplasm.neoplasm.
A tumor that grows indefinitely and A tumor that grows indefinitely and spreads (metastasis) is called spreads (metastasis) is called malignantmalignant----also called cancer.also called cancer.
A tumor that is not capable of indefinite A tumor that is not capable of indefinite growth----growth----benign.benign.
Malignant---kills host.Malignant---kills host. Benign---does not kill host.Benign---does not kill host.
Types of CancerTypes of Cancer CarcinomaCarcinoma: Cancer of endo or ectoderm : Cancer of endo or ectoderm
e.g. Skin or epithelial lining of organse.g. Skin or epithelial lining of organs SarcomasSarcomas: Cancer of mesoderm e.g. bone: Cancer of mesoderm e.g. bone Leukemias and LymphomasLeukemias and Lymphomas: Cancers of : Cancers of
hematopoietic cellshematopoietic cells
Cell GrowthCell Growth
Control of cell growth
Growth-promotingProto-oncogenes
Growth-restrictingTumor-suppressor genes
Molecular Basis of CancerMolecular Basis of Cancer
Uncontrolled cell growth
Proto-oncogenesTumor-suppressor genes
MutationsRadiationChemicalsVirus
Do tumors express foreign Ags?Do tumors express foreign Ags?
Transfertumor
H-2kH-2b
Rejects tumor
SummarySummary
When a tumor from H-2When a tumor from H-2k k mouse was mouse was injected into H-2injected into H-2bb mouse, it was rejected. mouse, it was rejected.
This experiment does not demonstrate This experiment does not demonstrate immunity against cancer.immunity against cancer.
Tumor was rejected due to expression of Tumor was rejected due to expression of foreign MHCforeign MHC
Syngeneic(accepted)
Allogeneic(rejected)
Inbred: repeated brother-sister matings
Outbred:normal population
Xenogeneic(rejected)
Ags expressed on tumor cellsAgs expressed on tumor cellsMajor HistocompatabilityComplex antigens
TAVA
TSTA
TADA
TSTA: unique to a tumor plays an important role in tumor rejection.
Tumor-specific transplantation AgTumor associateddevelopmental Ag
Tumor associated viral Ag
Demonstration of TSTADemonstration of TSTA
Induce tumors with chemicals (carcinogens) e.g. methylcholanthrene, benzopyrene
No tumor growth
control
tumor grows
Remove tumor, irradiate andinject into syngeneicmice
Inject viable tumor cells into normal or immunized mice
Immunized mouse
SummarySummary
Mice immunized with Mice immunized with syngeneicsyngeneic irradiated irradiated tumor cells could reject the same live tumor cells could reject the same live tumor upon rechallenge.tumor upon rechallenge.
However, an unimmunized mouse However, an unimmunized mouse developed tumor and died.developed tumor and died.
Because this experiment was done in a Because this experiment was done in a syngeneic mouse, tumors express TSTA.syngeneic mouse, tumors express TSTA.
Chemically induced cancers Chemically induced cancers
Each tumor induced by a carcinogen Each tumor induced by a carcinogen expresses a unique Ag.expresses a unique Ag.
Thus difficult to develop vaccine.Thus difficult to develop vaccine.
Tumor-Associated Developmental AgsTumor-Associated Developmental Ags
Found on cancer cells and on fetal cells.Found on cancer cells and on fetal cells. Do not trigger anti-tumor immunity.Do not trigger anti-tumor immunity. Used in diagnosis.Used in diagnosis. Alpha-fetoprotein(AFP) Cancers of Alpha-fetoprotein(AFP) Cancers of
liverliver Carcinoembryonic Ag (CEA) colorectal Carcinoembryonic Ag (CEA) colorectal
cancercancer
Other Tumor associated antigensOther Tumor associated antigens Silent gene-encoded Ags e.g. Thymic leukemic antigen Silent gene-encoded Ags e.g. Thymic leukemic antigen
(Tla) expressed in thymocytes of some strains(Tla) expressed in thymocytes of some strains Differentiation Ags: B cells produce surface Ig. Differentiation Ags: B cells produce surface Ig.
B cell tumors have sIgB cell tumors have sIg
Melanomas and melanocytes express MART-1Melanomas and melanocytes express MART-1 Overexpression of Ag on tumors compared to normal Overexpression of Ag on tumors compared to normal
cells e.g. In Breast cancer, HER2/neu homologous to cells e.g. In Breast cancer, HER2/neu homologous to Epidermal Growth Factor Receptor (EGFR)Epidermal Growth Factor Receptor (EGFR)
Abnormal posttranslational modifications. Abnormal posttranslational modifications. Underglycosylated mucin (MUC-1) e.g. breast cancerUnderglycosylated mucin (MUC-1) e.g. breast cancer
Ags expressed on male germ cells (lack MHC) and Ags expressed on male germ cells (lack MHC) and melanoma e.g. MAGE-1melanoma e.g. MAGE-1
Virally induced tumorsVirally induced tumors
Types:Types: DNA viruses: papova (SV40, polyoma, DNA viruses: papova (SV40, polyoma,
papilloma), hepatitis, adenovirus.papilloma), hepatitis, adenovirus. RNA viruses: Retroviruses---> Human T-RNA viruses: Retroviruses---> Human T-
lymphotropic viruses (HTLV-I and lymphotropic viruses (HTLV-I and HTLV-II).HTLV-II).
Induce a strong immune response.Induce a strong immune response.
Feline leukemia
Latentor recovered
Oncogenic disease
Non-oncogenic disease
Feline leukemia VirusFeline leukemia Virus Transmitted from cat to cat through saliva Transmitted from cat to cat through saliva
or transplacentallyor transplacentally Cats produce virus neutralizing Abs and Cats produce virus neutralizing Abs and
/or anti-tumor Abs/or anti-tumor Abs If both Abs are produced, cats recover.If both Abs are produced, cats recover. If only anti-tumor Abs are produced, they If only anti-tumor Abs are produced, they
get non-oncogenic disease.get non-oncogenic disease. If both Abs are not produced, cats get If both Abs are not produced, cats get
oncogenic disease.oncogenic disease.
UV-induced tumorsUV-induced tumors
>800,000 cases of skin cancer/year.>800,000 cases of skin cancer/year. UV radiation--->most serious skin UV radiation--->most serious skin
cancer--->melanomascancer--->melanomas Highly immunogenic.Highly immunogenic.
SummarySummary
A tumor grows in syngeneic host but not A tumor grows in syngeneic host but not in allogeneic or xenogeneic hostsin allogeneic or xenogeneic hosts
Tumor Ags expressed may be specific to Tumor Ags expressed may be specific to a tumor cell or shared with other cellsa tumor cell or shared with other cells
Evidence for the role of immune system in tumor rejection
Evidence for the role of immune system in tumor rejection
Spontaneous regressionSpontaneous regression Regression of metastases after removal of Regression of metastases after removal of
primary tumorprimary tumor Regression after chemotherapyRegression after chemotherapy Infiltration of tumors by lymphocytes and Infiltration of tumors by lymphocytes and
macrophagesmacrophages Lymphocyte proliferation in draining lymph Lymphocyte proliferation in draining lymph
nodesnodes Higher incidence of cancer after Higher incidence of cancer after
immunosuppression, immunodeficiency immunosuppression, immunodeficiency (AIDS, neonates), aging, etc.(AIDS, neonates), aging, etc.
Requirements for effective immune response against tumors
Requirements for effective immune response against tumors
Tumor should express a foreign Ag.Tumor should express a foreign Ag. Tumor should be immunogenic.Tumor should be immunogenic. Host should be immunocompetent.Host should be immunocompetent. Immune response should not result in Immune response should not result in
tolerance.tolerance. Tumor should not change Ag.Tumor should not change Ag.
Immunity against tumorsImmunity against tumors
tumormacrophage
T helper (Th) cell
B cell
tumor
CTL
tumor AgClass I MHC
NK
FasL Fas
CTL Tumor
Perforin/granzyme
NK
Apoptosis
T lymphocytesT lymphocytes
CD4 CD8
T helper T cytotoxic
Tumor Tumor
ClassI MHCClassII MHC
AgAg
Produce factors that activate other cells to kill tumor cells Directly kill Cl II+ tumor cells
Lyse tumor cells
T cell receptor (TCR)
Role of CTLRole of CTL
TSTA is processed and presented with TSTA is processed and presented with Class I MHC to CTLClass I MHC to CTL
CTL produce FasL or perforin/granzyme CTL produce FasL or perforin/granzyme which kills the tumor cell. which kills the tumor cell.
If tumor cells are Fas+ve, CTL will use If tumor cells are Fas+ve, CTL will use FasL to kill tumor cell apoptosis.FasL to kill tumor cell apoptosis.
Role of Th cellsRole of Th cells TSTA shed by cancer cells, is processed and TSTA shed by cancer cells, is processed and
presented by B cells or macrophages to Th presented by B cells or macrophages to Th cellscells
Th cells will activate B cells or macrophages Th cells will activate B cells or macrophages by producing cytokines.by producing cytokines.
Abs are not very effective against cancer Abs are not very effective against cancer except against retrovirally induced tumors.except against retrovirally induced tumors.
Activated macrophages can kill the tumor Activated macrophages can kill the tumor cells.cells.
B Lymphocytes B Lymphocytes
sIg
Tumor
Complement
Natural Killer cell/Macrophage/Granulocyte
FcRFabFc
Tumor
Ab dependent cell cytotoxicity(ADCC)
Ag
Role of NK cellsRole of NK cells NK cells can recognize MHC -ve tumor NK cells can recognize MHC -ve tumor NK cells are large granular lymphocytes NK cells are large granular lymphocytes
(LGL) TCR(LGL) TCR--, asialoGM, asialoGM++ or NK1.1 or NK1.1++.. It is not known exactly how NK cells It is not known exactly how NK cells
recognize tumor cells.recognize tumor cells. Lyse virally-infected cells and tumor cellsLyse virally-infected cells and tumor cells Spontaneous cytotoxicity/ADCCSpontaneous cytotoxicity/ADCC Activity increased by interleukin (IL)-2 = Activity increased by interleukin (IL)-2 =
lymphokine-activated killer cells (LAK)lymphokine-activated killer cells (LAK) They use FasL and perforin to kill tumor They use FasL and perforin to kill tumor
cells.cells.
MacrophagesMacrophages Normal MNormal M not tumoricidal not tumoricidal Activated MActivated Mare tumoricidalare tumoricidal Direct cytotoxicity or ADCCDirect cytotoxicity or ADCC Reactive oxygen intermediates (OReactive oxygen intermediates (O--, H, H22OO22))
Nitric oxide (NO)Nitric oxide (NO) Tumor necrosis factor (TNF)Tumor necrosis factor (TNF) Lysosomal enzymes Lysosomal enzymes Antigen processing and presentationAntigen processing and presentation
How does a tumor escape immune recognition?How does a tumor escape immune recognition?
Generation of suppressor cellsGeneration of suppressor cells Secrete immunosuppressive molecules Secrete immunosuppressive molecules
Ex: prostaglandins, transforming growth Ex: prostaglandins, transforming growth factor beta (TGF-factor beta (TGF-), IL-10, etc.), IL-10, etc.
Tumor T regulatory
MCTL
Tumors may fail to process and present Tumors may fail to process and present Ag.Ag.
Downregulation of MHC expression on Downregulation of MHC expression on tumor cell (CTL resistant but NK tumor cell (CTL resistant but NK sensitive)sensitive)
Tumors may fail to express Tumors may fail to express adhesion/costimulatory molecules adhesion/costimulatory molecules involved in T cell activation.involved in T cell activation.
Tumors escape the action of CTL by not expressing B7 molecule involved in T cell activation
tumor
CTL
tumor Ag
Class I MHC
B7
CD28
Tumor escape mechanisms:Tumor escape mechanisms:Fas FasL
TumorCTL
FasFasL
TumorCTL
When tumor cells express Fas Ligand,they can kill Fas+T cells, thereby escapingimmune destruction.
Ag masking: sialic acid, mucin, fibrin coating
Tolerance of host to tumor Ags - Tolerance of host to tumor Ags - Neonatal exposure e.g. murine mammary Neonatal exposure e.g. murine mammary tumor virustumor virus
Tolerogenic Ags of tumor (high dose/low Tolerogenic Ags of tumor (high dose/low dose or no costimulators)dose or no costimulators)
Tumor
Mutation in tumor cells with loss of Mutation in tumor cells with loss of antigen expressionantigen expression
Antigenic modulationAntigenic modulation: Ab binding leads : Ab binding leads to endocytosis or shedding of Ag-Ab to endocytosis or shedding of Ag-Ab complexes.complexes.
Blocking FactorsBlocking Factors: Shed Ag or Ag-Ab : Shed Ag or Ag-Ab complexes act as blocking factors . Block complexes act as blocking factors . Block FcR of NK or induce suppressor cellsFcR of NK or induce suppressor cells
Cancer TherapyCancer Therapy Surgery - Surgery -
Localized tumorsLocalized tumors Radiation - Radiation -
Metastastic tumorsMetastastic tumors Affects proliferating cells (bone marrow, etc.) Affects proliferating cells (bone marrow, etc.) Radiation-resistant tumors developRadiation-resistant tumors develop
Chemotherapy - Chemotherapy - Metastastic tumorsMetastastic tumors Affects proliferating cells (bone marrow, etc.) Affects proliferating cells (bone marrow, etc.) Drug-resistant tumors developDrug-resistant tumors develop
Immunotherapy -Immunotherapy - Metastastic tumorsMetastastic tumors SpecificitySpecificity Do not develop resistanceDo not develop resistance No toxicityNo toxicity
ImmunotherapyImmunotherapy Active ImmunizationActive Immunization: :
SpecificSpecific Vaccination with viral Ags: e.g.Vaccination with viral Ags: e.g.
Feline leukemia virus (FLV)Feline leukemia virus (FLV)Herpes - Marek’s disease of chickens Herpes - Marek’s disease of chickens Hepatitis B virus.Hepatitis B virus.
Haptenated tumor cells (trinitrophenol - Haptenated tumor cells (trinitrophenol - TNP)TNP)
Costimulator (B7) transfected tumor cellsCostimulator (B7) transfected tumor cells
tumorCTL
CD28
Tumors escape the action of CTL by not expressing B7 molecule
tumor
B7 CD28
CTL
No killing
killing
Use of B7 to induce anti-tumor immunity
B7-ve tumorDies
SurvivesB7+ve tumor
tumor
Use of MAGE as a vaccine against melanomasUse of MAGE as a vaccine against melanomas
Expressed on normal melanocytes and Expressed on normal melanocytes and melanomas – Vitiligo (skin depigmentation)melanomas – Vitiligo (skin depigmentation)
MAGE
NonspecificNonspecific:: BCG (Bacillus Calmette-Guerin) BCG (Bacillus Calmette-Guerin)
Mycobacteria - melanoma, bladder Mycobacteria - melanoma, bladder carcinomacarcinoma
Corynebacterium parvum (C. parvum)Corynebacterium parvum (C. parvum) Muramyl dipeptideMuramyl dipeptide
Normal M
Tumor
Activated M
Tumor lysis
Anti-CD3 Abs - polyclonal activation of T Anti-CD3 Abs - polyclonal activation of T cellscells
CD3
TCR
TumorT cell T cell Tumor
CD3
TCR
Tumor Ag
MHCMHC
Tumor Ag
Anti-CD3T cell Activation
Passive ImmunizationPassive Immunization Specific:Specific: Ab Therapy Ab Therapy
Anti-idiotypic AbsAnti-idiotypic Abs
Abs against growth factor receptor e.g. IL-2R Abs against growth factor receptor e.g. IL-2R in HTLV-1 induced Adult T cell leukemiain HTLV-1 induced Adult T cell leukemia
Abs specific for oncogene product e.g. Abs Abs specific for oncogene product e.g. Abs against HER2/against HER2/neu (neu (Herceptin or trastuzumab)Herceptin or trastuzumab)
B celltumor
Idiotype
B cell
IL-2R
IL-2
Anti-IL-2R
Monoclonal Abs used in Immunotherapy
Monoclonal Abs used in Immunotherapy
Unlabelled Ab: e.g. Anti-CD20 Ab in Unlabelled Ab: e.g. Anti-CD20 Ab in non-Hodgkin’s lymphoma non-Hodgkin’s lymphoma
C’C’ ADCCADCC
Labelled Ab (Radioisotope/Toxin)Labelled Ab (Radioisotope/Toxin) 131131I (Iodine)I (Iodine) InternalizationInternalization
Anti-tumor Abs coupled to toxin, Anti-tumor Abs coupled to toxin, radioisotopes, drugs or enzymesradioisotopes, drugs or enzymes::
ImmunotoxinsImmunotoxins: : Ricin A/diphtheria/Pseudomonas Ricin A/diphtheria/Pseudomonas toxin coupled to Abs. e.g. antiCD22-toxin coupled to Abs. e.g. antiCD22-Psudomonas toxin in hairy (B) cell Psudomonas toxin in hairy (B) cell leukemia leukemia Toxin inhibits protein synthesis.Toxin inhibits protein synthesis.Cytocidal isotopes or anticancer Cytocidal isotopes or anticancer drugs (adriamycin) coupled to Absdrugs (adriamycin) coupled to Abs
TumorRicin
ProdrugDrug
Ab-Enzyme
Inefficacy of Abs Tumor Ags + Class I MHCTumor Ags + Class I MHC Shedding/internalization of tumor Ag/Ag-Ab Shedding/internalization of tumor Ag/Ag-Ab
complexescomplexes Noncytotoxic Abs (C’/ADCC) Noncytotoxic Abs (C’/ADCC) Anti-rat/mouse Ab develops causing Anti-rat/mouse Ab develops causing
anaphylaxis and serum sicknessanaphylaxis and serum sickness ––Humanized/chimeric Ab (from 2 species)Humanized/chimeric Ab (from 2 species)
Human Fc
Mouse Fab
T cell Tumorcell
CD3Ag
Bispecific Ab Humanized Ab
Half life of AbHalf life of Ab Non specific binding to FcR+ cells (MNon specific binding to FcR+ cells (M, ,
granulocytes, NK and B cells)granulocytes, NK and B cells)
M
Adoptive Immunotherapy
1. 1. Lymphokine-activated killer cells Lymphokine-activated killer cells (LAK): (LAK): PBL + high dose IL-2PBL + high dose IL-2
NKNK LAKLAK
2. 2. Tumor-infiltrating lymphocytes Tumor-infiltrating lymphocytes (TIL): (TIL):
In and around solid tumorsIn and around solid tumors
Activated NK and CTLActivated NK and CTL
1)Use of LAK cells + IL-2 to treat cancer1)Use of LAK cells + IL-2 to treat cancer
Isolate lymphocytes from blood
lymphocytes
+IL-2 for 3 days
IL-2
LAKcells
melanoma
Immunotherapy of CancerImmunotherapy of Cancer
Treatment of Melanoma with LAK cells +IL-2
Treatment of Melanoma with LAK cells +IL-2
Before After
2) Use of tumor-infiltrating lymphocytes + IL-2 to treat cancer2) Use of tumor-infiltrating lymphocytes + IL-2 to treat cancer
surgical removalof cancer nodule
tumor
T cell
+IL-2
IL-2
Successful treatment of melanoma and renal cell carcinoma
Treatment of Melanomas with TIL + IL-2
Treatment of Melanomas with TIL + IL-2
Before After
Problems associated with IL-2 therapy
Problems associated with IL-2 therapy
Very toxic----triggers vascular leak.Very toxic----triggers vascular leak.
IL-2
T cell
CD44
endothelial cells
Dendritic CellsDendritic Cells Highly potent antigen processing and Highly potent antigen processing and
presenting cellspresenting cells Prime an Immune ResponsePrime an Immune Response Pulse with tumor Ags or gene transferPulse with tumor Ags or gene transfer
Cl II Cl I
Autologous bone marrow (treated Autologous bone marrow (treated in vitro in vitro with Ab + C) transplantation following with Ab + C) transplantation following irradiation.irradiation.
Allogeneic bone marrow transplantation Allogeneic bone marrow transplantation (matching 1 or 2 HLA Ag) – Graft versus (matching 1 or 2 HLA Ag) – Graft versus host reactionhost reaction
Cytokine Therapy
Inj. cytokines.Inj. cytokines.
1.1. Interleukin -2 (IL-2) high dose - Alone Interleukin -2 (IL-2) high dose - Alone or or with cellswith cells
Melanoma and renal cell carcinomaMelanoma and renal cell carcinoma
Activates NK and CTLActivates NK and CTL
Toxic - fever, edema, shockToxic - fever, edema, shock
IL-4IL-4
2.2. Tumor necrosis factor (TNF) - Tumor necrosis factor (TNF) - CarcinomaCarcinoma
3.3. Interferon (IFN)-Interferon (IFN)- Produced by Leukocytes Produced by Leukocytes
Activates NK activityActivates NK activity
Increases class I MHCIncreases class I MHC
Hairy cell leukemia, renal cell carcinoma, Hairy cell leukemia, renal cell carcinoma, melanoma, Kaposi sarcoma, hematologic melanoma, Kaposi sarcoma, hematologic cancerscancers
4.4. IFN-IFN- : Ovarian carcinoma : Ovarian carcinoma
5.5. Hematopoietic growth factors: Hematopoietic growth factors: Overcome neutropeniaOvercome neutropenia
Granulocyte-macrophage colony stimulating Granulocyte-macrophage colony stimulating factor (GM-CSF)factor (GM-CSF)
Granulocyte colony stimulating factor Granulocyte colony stimulating factor
(G-CSF)(G-CSF)
Gene therapyGene therapyIntroduce cytokine genes for IL-2, IL-4, IL-12,GM-CSF or IFN-into tumor cells.
Tumor Ag gene expressed in DC (Tumor Ag Tumor Ag gene expressed in DC (Tumor Ag usually not known).usually not known).
tumorT cell
M
IL-2IL-4
GM-CSF
SUMMARYSUMMARY
Tumors should express TSTA.Tumors should express TSTA. T cells are important in tumor rejection.T cells are important in tumor rejection. NK cells and macrophages also play an NK cells and macrophages also play an
important role.important role. Tumors evade immune system in a Tumors evade immune system in a
number of ways.number of ways. Immunotherapy is promising.Immunotherapy is promising.
Immunotherapy of CancerImmunotherapy of Cancer Manipulation of the host’s immune system to Manipulation of the host’s immune system to
treat cancer.treat cancer. Treatment with IL-2---to activate NK/LAK Treatment with IL-2---to activate NK/LAK
cells.cells. Culture and transfer of tumor infiltrating Culture and transfer of tumor infiltrating
lymphocytes.lymphocytes. ImmunotoxinsImmunotoxins Cytokine gene-therapyCytokine gene-therapy Dendritic cell therapyDendritic cell therapy Bone marrow transplantationBone marrow transplantation Anti -idiotypic Abs against myelomas.Anti -idiotypic Abs against myelomas.
Suggested ReadingSuggested Reading
Immunobiology: The Immune System in Immunobiology: The Immune System in Health and Disease by Janeway et al. 6Health and Disease by Janeway et al. 6 thth edition, 2005. Pg. 630-642edition, 2005. Pg. 630-642