Date post: | 11-May-2015 |
Category: |
Health & Medicine |
Upload: | many87 |
View: | 2,997 times |
Download: | 3 times |
Mitzi Nagarkatti, PhDMitzi Nagarkatti, PhDProfessor and Chair Professor and Chair
Dept. of Pathology, Microbiology and ImmunologyDept. of Pathology, Microbiology and ImmunologySchool of MedicineSchool of Medicine
andandDeputy Director, Basic and Translational Research Deputy Director, Basic and Translational Research
South Carolina Cancer CenterSouth Carolina Cancer CenterUniversity of South CarolinaUniversity of South Carolina
Tel. # (803)733-3275Tel. # (803)733-3275E-mail: [email protected]: [email protected]
Tumor Immunology
ObjectivesObjectives
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 often A tumor that grows indefinitely and often 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.
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
MutationsRadiationChemical (Carcinogen)Virus
Types of cancers based on etiologic agentTypes of cancers based on etiologic agent Chemically-induced tumorsChemically-induced tumors
Each tumor induced by a carcinogen (e.g. benzopyrene) Each tumor induced by a carcinogen (e.g. benzopyrene) injected at various sites expresses a unique Ag.injected at various sites expresses a unique Ag.
Thus difficult to develop vaccine.Thus difficult to develop vaccine.
Virus-induced tumorsVirus-induced tumors Tumors induced by same virus express same tumor Ag.Tumors induced by same virus express same tumor Ag. Induce a strong immune response.Induce a strong immune response.
e.g. Gardasil vaccine – Human Papilloma Virus (HPV) e.g. Gardasil vaccine – Human Papilloma Virus (HPV) induced cervical cancerinduced cervical cancer
UV-induced tumorsUV-induced tumors UV radiation--->melanomasUV radiation--->melanomas Highly tumorigenicHighly tumorigenic
Virus-induced tumors e.g.SV40
Chemical-induced tumors e.g. methylcholanthrene
Types of Cancer based on the tissue affectedTypes of Cancer based on the tissue affected 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
Evidence for the role of immune system in tumor rejection
Evidence for the role of immune system in tumor rejection
Spontaneous regressionSpontaneous regression Infiltration of tumors by lymphocytes and Infiltration of tumors by lymphocytes and
macrophagesmacrophages Regression of metastases after removal of Regression of metastases after removal of
primary tumorprimary tumor Regression after chemotherapyRegression after chemotherapy 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, aged, transplant patients)(AIDS, neonates, aged, transplant patients)
Antigens expressed on tumor cellsAntigens expressed on tumor cells
Major HistocompatabilityComplex antigens
TSTA
TATA
TSTA: unique to a tumor Play an important role in tumor rejection.TATA: shared by normal and tumor cells
Tumor-associated developmental Ag (TADA)Tumor-associated viral Ag (TAVA)
Tumor-specific transplantation AgTumor-associatedtransplantation Ag
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 liverAlpha-fetoprotein(AFP) Cancers of liver Carcinoembryonic Ag (CEA) colorectal Carcinoembryonic Ag (CEA) colorectal
cancercancer
Other Tumor associated antigensOther Tumor associated antigens 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 Overexpression of Ag on tumors compared to
normal cells e.g. In breast cancer, HER2/neunormal cells e.g. In breast cancer, HER2/neu Ags expressed on male germ cells and melanoma Ags expressed on male germ cells and melanoma
e.g. MAGE-1e.g. MAGE-1
Syngeneic(accepted)
Allogeneic(rejected)
Inbred: repeated brother-sister matings
Outbred:normal population
Xenogeneic(rejected)
Tumor Growth
Across SpeciesRat
Mouse
How does a tumor escape immune surveillance?How does a tumor escape immune surveillance?
Generation of Regulatory cells (CD4Generation of Regulatory cells (CD4+CD25CD25+ FoxP3 FoxP3+ T T cells) or Myeloid-derived suppressor cells(Gr-1cells) or Myeloid-derived suppressor cells(Gr-1+ + CD11bCD11b++))
Secrete immunosuppressive molecules Ex: Secrete immunosuppressive molecules Ex: Transforming growth factor beta (TGF-Transforming growth factor beta (TGF-), interleukin-), interleukin-10 (IL-10), etc.10 (IL-10), etc.
Tumor
T regs
MDSC
CTL
IL-10, etc
Failure to process and present tumor Ag.Failure to process and present tumor Ag.
tumor
Macrophage
T helper (Th) cell
B cell
Cytotoxic T lymphocyte (CTL)
tumor Ag tumor
tumor
MHC Class I
MHC Class II
Tumors escape the action of CTL by not expressing B7 which provides 2nd signal involved in T cell activation
tumor
CTL
tumor Ag
Class I MHC
B7
CD28
Tumors may fail to express costimulatory Tumors may fail to express costimulatory
molecules involved in T cell activation.molecules involved in T cell activation.
Downregulation of MHC expression on Downregulation of MHC expression on tumor cell (CTL resistant but NK tumor cell (CTL resistant but NK sensitive)sensitive)
NK cellTumor
cell
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.
Surgery Surgery Radiation ChemotherapyRadiation Chemotherapy
Localized tumors Metastastic tumorsAffects proliferating cells
(bone marrow, etc.) Radiation/Drug-resistant tumors
Novel Mode: Immunotherapy
Traditional approaches to treat cancer
ImmunotherapyImmunotherapy Active ImmunizationActive Immunization: The host actively elicits : The host actively elicits
an immune response. an immune response. SpecificSpecific
Vaccination with viral Ags: e.g.Vaccination with viral Ags: e.g. Hepatitis B virusHepatitis B virus Human Papilloma virus (HPV) - Human Papilloma virus (HPV) -
GardasilGardasil
NonspecificNonspecific:: BCG (Bacillus Calmette-Guerin) BCG (Bacillus Calmette-Guerin)
Mycobacteria - melanoma, bladder Mycobacteria - melanoma, bladder carcinomacarcinoma
Normal M
Tumor
Activated M
Tumor lysis
Passive ImmunizationPassive Immunization: Preformed Abs or immune : Preformed Abs or immune cells transferredcells transferred Specific:Specific: Ab Therapy Ab Therapy
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)
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
Complement (C’)Complement (C’) Ab-dependent cell mediated Ab-dependent cell mediated
cytotoxicity (ADCC)cytotoxicity (ADCC) Labelled Ab (Radioisotope/Toxin)Labelled Ab (Radioisotope/Toxin)
131131I (Iodine)I (Iodine) InternalizationInternalization
B cell tumor
C’
M/NK/PMN
CD20
FcR
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. antiCD20-toxin coupled to Abs. e.g. antiCD20-Pseudomonas toxin in B cell Pseudomonas toxin in B cell leukemia leukemia Internalized toxin inhibits protein Internalized toxin inhibits protein synthesis.synthesis.Cytocidal isotopes or anticancer Cytocidal isotopes or anticancer drugs (adriamycin) coupled to Absdrugs (adriamycin) coupled to Abs
TumorRicin
Adoptive ImmunotherapyAdoptive Immunotherapy
1. 1. Lymphokine-activated killer cells Lymphokine-activated killer cells (LAK): (LAK): Peripheral Blood Lymphocyte (PBL) + Peripheral Blood Lymphocyte (PBL) + high dose IL-2high dose IL-2
NK/TNK/T 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
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
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/chemotherapy.irradiation/chemotherapy.
Allogeneic bone marrow transplantation Allogeneic bone marrow transplantation (matched for HLA Ag) – Graft versus (matched for HLA Ag) – Graft versus host reactionhost reaction
Cytokine TherapyCytokine Therapy
Inject cytokines.Inject 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
2.2. Tumor necrosis factor (TNF-Tumor necrosis factor (TNF-) - ) - CarcinomaCarcinoma
3.3. Interferon (IFN)-Interferon (IFN)- Activates NK activityActivates NK activity
Hairy B cell leukemia, renal cell carcinoma, Hairy B cell leukemia, renal cell carcinoma, melanoma, Kaposi sarcoma, hematologic melanoma, Kaposi sarcoma, hematologic cancerscancers
4.4. IFN-IFN- : Increases Cl II MHC expression. : Increases Cl II MHC expression. Ovarian carcinomaOvarian 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)
Gene therapyGene therapyIntroduce cytokine genes for IL-2, IL-4, IL-12, IFN- or GM-CSF into tumor cells.
tumorT cell
M
IL-2
GM-CSF
SUMMARYSUMMARY
Tumors should express TSTA.Tumors should express TSTA. Th cells and CTL are important in tumor Th cells and CTL are important in tumor
rejection.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.
Reading Reading Immunology By Male, Brostoff, Roth and Roitt7th EditionPages 401-419