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Cancer Immunology

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Melanomas and melanocytes express MART-1 ... Hairy B cell leukemia, renal cell carcinoma, melanoma, Kaposi sarcoma, hematologic cancers ... – PowerPoint PPT presentation

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Title: Cancer Immunology


1
Tumor Immunology
Mitzi Nagarkatti, PhD Professor and Chair Dept.
of Pathology, Microbiology and Immunology School
of Medicine and Deputy Director, Basic Research
South Carolina Cancer Center University of South
Carolina Tel. (803)733-3275 E-mail
mnagark_at_med.sc.edu
2
Cancer Immunology
  • Introduction
  • Ags expressed by cancer cells
  • Nature of immune response
  • How cancer evades immune system
  • Immunotherapy

3
Cancer Introduction
  • Uncontrolled growth produces a tumor or neoplasm.
  • A tumor that grows indefinitely and often spreads
    (metastasis) is called malignant--also called
    cancer.
  • A tumor that is not capable of indefinite
    growth----benign.
  • Malignant---kills host.
  • Benign---does not kill host.

4
Cell Growth
Control of cell growth
Growth-restricting Tumor-suppressor genes
Growth-promoting Proto-oncogenes
5
Molecular Basis of Cancer
Radiation Chemicals Virus
Mutations
Uncontrolled cell growth
Proto-oncogenes
Tumor-suppressor genes
6
Types of Cancer based on the tissue affected
  • Carcinoma Cancer of endo or ectoderm e.g. Skin
    or epithelial lining of organs
  • Sarcomas Cancer of mesoderm e.g. bone
  • Leukemias and Lymphomas Cancers of hematopoietic
    cells

7
Types of cancers based on etiologic agent
  • Chemically-induced tumors
  • Each tumor induced by a carcinogen (benzopyrene)
    injected at various sites expresses a unique Ag.
  • Thus difficult to develop vaccine.
  • Virus-induced tumors
  • Tumors induced by same virus express same tumor
    Ag.
  • Induce a strong immune response.
  • e.g. Gardasil Human Papilloma Virus (HPV)
    induced cervical cancer
  • UV-induced tumors
  • UV radiation---gtmelanomas

8
Evidence for the role of immune system in tumor
rejection
  • Spontaneous regression
  • Regression of metastases after removal of primary
    tumor
  • Regression after chemotherapy
  • Infiltration of tumors by lymphocytes and
    macrophages
  • Lymphocyte proliferation in draining lymph nodes
  • Higher incidence of cancer after
    immunosuppression/immunodeficiency (AIDS,
    neonates, aged, transplant patients)

9
Antigens expressed on tumor cells
Major Histocompatability Complex antigens
TSTA
Tumor-specific transplantation Ag
TATA
Tumor-associated transplantation Ag
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)
10
Tumor-Associated Developmental Ags
  • Found on cancer cells and on fetal cells.
  • Do not trigger anti-tumor immunity.
  • Used in diagnosis.
  • Alpha-fetoprotein(AFP) Cancers of
    liver
  • Carcinoembryonic Ag (CEA) colorectal cancer

11
Other Tumor associated antigens
  • Differentiation Ags B cells produce surface Ig.
    B cell tumors have sIg
  • Melanomas and melanocytes express MART-1
  • Overexpression of Ag on tumors compared to normal
    cells e.g. In breast cancer, HER2/neu
  • Ags expressed on male germ cells and melanoma
    e.g. MAGE-1

12
Inbred repeated brother-sister matings
Tumor Growth
Syngeneic (accepted)
Outbred normal population
Allogeneic (rejected)
Across Species
Xenogeneic (rejected)
13
How does a tumor escape immune surveillance?
  • Generation of regulatory cells (CD4CD25 FoxP3
    T cells)
  • Secrete immunosuppressive molecules
  • Ex prostaglandins, transforming growth factor
    beta (TGF-b), interleukin-10 (IL-10), etc.

T regs
CTL
MF
IL-10, etc
14
  • Failure to process and present tumor Ag.

Macrophage
tumor Ag
tumor
B cell
MHC Class II
T helper (Th) cell
MHC Class I
Cytotoxic T lymphocyte (CTL)
tumor
tumor
15
  • Downregulation of MHC expression on tumor cell
    (CTL resistant but NK sensitive)

NK cell
Tumor cell
16
  • Tumors may fail to express costimulatory
  • molecules involved in T cell activation.

Tumors escape the action of CTL by not expressing
B7 which provides 2nd signal involved in T cell
activation
17
Tumor escape mechanisms
FasL
Fas
Tumor
CTL
FasL
Fas
Tumor
CTL
When tumor cells express Fas Ligand, they can
kill Fas T cells, thereby escaping immune
destruction.
18
Traditional approaches to treat cancer
Surgery Radiation Chemotherapy
Localized tumors Metastastic tumors Affects
proliferating cells (bone marrow, etc.)
Radiation/Drug-resistant tumors Novel Mode
Immunotherapy
19
Immunotherapy
  • Active Immunization
  • Specific
  • Vaccination with viral Ags e.g.
  • Hepatitis B virus
  • Human Papilloma virus (HPV)

20
  • Nonspecific
  • BCG (Bacillus Calmette-Guerin) Mycobacteria -
    melanoma, bladder carcinoma

21
  • Passive Immunization
  • Specific Ab Therapy
  • Abs against growth factor receptor e.g. IL-2R in
    HTLV-1 induced Adult T cell leukemia
  • Abs specific for oncogene product e.g. Abs
    against HER2/neu (Herceptin or trastuzumab)

IL-2R
Anti-IL-2R
IL-2
22
Monoclonal Abs used in Immunotherapy
  • Unlabelled Ab e.g. Anti-CD20 Ab in non-Hodgkins
    lymphoma
  • Complement (C)
  • Ab-dependent cell mediated cytotoxicity (ADCC)
  • Labelled Ab (Radioisotope/Toxin)
  • 131I (Iodine)
  • Internalization

C
B cell tumor
CD20
FcR
Mf/NK/ PMN
23
  • Anti-tumor Abs coupled to toxin, radioisotopes,
    drugs or enzymes
  • Immunotoxins
  • Ricin A/diphtheria/Pseudomonas toxin coupled to
    Abs. e.g. antiCD20-Pseudomonas toxin in B cell
    leukemia
  • Internalized toxin inhibits protein synthesis.
  • Cytocidal isotopes or anticancer drugs
    (adriamycin) coupled to Abs

Tumor
Ricin
24
Adoptive Immunotherapy
  • 1. Lymphokine-activated killer cells (LAK)
    Peripheral Blood Lymphocyte (PBL) high dose
    IL-2
  • NK/T LAK
  • 2. Tumor-infiltrating lymphocytes (TIL)
  • In and around solid tumors
  • Activated NK and CTL

25
1)Use of LAK cells IL-2 to treat cancer
Immunotherapy of Cancer
IL-2
Isolate lymphocytes from blood
lymphocytes
melanoma
IL-2 for 3 days
LAK cells
26
Treatment of Melanoma with LAK cells IL-2
Before
After
27
2) Use of tumor-infiltrating lymphocytes IL-2
to treat cancer
IL-2
surgical removal of cancer nodule
T cell
tumor
IL-2
Successful treatment of melanoma and renal cell
carcinoma
28
Treatment of Melanomas with TIL IL-2
Before
After
29
Dendritic Cells
  • Highly potent antigen processing and presenting
    cells
  • Prime an Immune Response
  • Pulse with tumor Ags or gene transfer

Cl II
Cl I
30
  • Autologous bone marrow (treated in vitro with Ab
    C) transplantation following
    irradiation/chemotherapy.
  • Allogeneic bone marrow transplantation (matching
    1 or 2 HLA Ag) Graft versus host reaction

31
Cytokine Therapy
  • Inject cytokines.
  • 1. Interleukin -2 (IL-2) high dose - Alone or
    with cells
  • Melanoma and renal cell carcinoma
  • Activates NK and CTL
  • Toxic - fever, edema, shock
  • 2. Tumor necrosis factor (TNF) - Carcinoma

32
  • 3. Interferon (IFN)-a
  • Activates NK activity
  • Hairy B cell leukemia, renal cell carcinoma,
    melanoma, Kaposi sarcoma, hematologic cancers
  • 4. IFN-g Increases Cl II MHC expression.
    Ovarian carcinoma
  • 5. Hematopoietic growth factors Overcome
    neutropenia
  • Granulocyte-macrophage colony stimulating
    factor (GM-CSF)

33
Gene therapy
Introduce cytokine genes for IL-2, IL-4, IL-12,
IFN-g or GM-CSF into tumor cells.
IL-2 GM-CSF
T cell
tumor
Mf
34
SUMMARY
  • Tumors should express TSTA.
  • T cells are important in tumor rejection.
  • NK cells and macrophages also play an important
    role.
  • Tumors evade immune system in a number of ways.
  • Immunotherapy is promising.

35
Reading
Immunology By Male, Brostoff, Roth and Roitt 7th
Edition Pages 401-419
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