Cancer Immunology

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Tumor Immunology
Mitzi Nagarkatti, PhD Professor and Chair Dept.
of Pathology, Microbiology and Immunology School
of Medicine and Deputy Director, Basic and
Translational Research South Carolina Cancer
Center University of South Carolina Tel.
[phone] E-mail mnagark_at_uscmed.sc.edu
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Objectives

• Introduction
• Ags expressed by cancer cells
• Nature of immune response
• How cancer evades immune system
• Immunotherapy

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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.

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Cell Growth
Control of cell growth
Growth-restricting Tumor-suppressor genes
Growth-promoting Proto-oncogenes
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Molecular Basis of Cancer
Radiation Chemical (Carcinogen) Virus
Mutations
Uncontrolled cell growth
Proto-oncogenes
Tumor-suppressor genes
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Types of cancers based on etiologic agent

• Chemically-induced tumors
• Each tumor induced by a carcinogen (e.g.
  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 vaccine Human Papilloma Virus
  (HPV) induced cervical cancer
• UV-induced tumors
• UV radiation---gtmelanomas
• Highly tumorigenic

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Virus-induced tumors e.g.SV40
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Chemical-induced tumors e.g. methylcholanthrene
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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

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Evidence for the role of immune system in tumor
rejection

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

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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)
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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

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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

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Inbred repeated brother-sister matings
Tumor Growth
Syngeneic (accepted)
Mouse
Outbred normal population
Allogeneic (rejected)
Across Species
Rat
Xenogeneic (rejected)
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How does a tumor escape immune surveillance?

• Generation of Regulatory cells (CD4CD25 FoxP3
  T cells) or Myeloid-derived suppressor
  cells(Gr-1 CD11b)
• Secrete immunosuppressive molecules Ex
  Transforming growth factor beta (TGF-b),
  interleukin-10 (IL-10), etc.

T regs
CTL
MDSC
IL-10, etc
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• 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
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• 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
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• Downregulation of MHC expression on tumor cell
  (CTL resistant but NK sensitive)

NK cell
Tumor cell
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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.
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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
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Immunotherapy

• Active Immunization The host actively elicits
  an immune response.
• Specific
• Vaccination with viral Ags e.g.
• Hepatitis B virus
• Human Papilloma virus (HPV) - Gardasil

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

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• Passive Immunization Preformed Abs or immune
  cells transferred
• 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)

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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
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• 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
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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

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1)Use of LAK cells IL-2 to treat cancer
IL-2
Isolate lymphocytes from blood
lymphocytes
melanoma
IL-2 for 3 days
LAK cells
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Treatment of Melanoma with LAK cells IL-2
Before
After
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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
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Treatment of Melanomas with TIL IL-2
Before
After
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Dendritic Cells

• Highly potent antigen processing and presenting
  cells
• Prime an Immune Response
• Pulse with tumor Ags or gene transfer

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

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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-a) - Carcinoma

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• 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)

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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
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SUMMARY

• Tumors should express TSTA.
• Th cells and CTL 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.

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