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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 University of South Carolina Cancer Center Tel. # (803)733-3275 E-mail: mnagark@uscmed.sc.edu.

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slide1

Tumor Immunology

Mitzi Nagarkatti, PhD

Professor and Chair

Dept. of Pathology, Microbiology and Immunology

School of Medicine

and

Deputy Director, Basic and Translational Research

University of South Carolina Cancer Center

Tel. # (803)733-3275

E-mail: mnagark@uscmed.sc.edu

objectives

Objectives

Introduction

Ags expressed by cancer cells

Nature of immune response

How cancer evades immune system

Immunotherapy

cancer introduction
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.
cell growth
Cell Growth

Control of cell

growth

Growth-restricting

Tumor-suppressor genes

Growth-promoting

Proto-oncogenes

molecular basis of cancer
Molecular Basis of Cancer

Radiation

Chemical (Carcinogen)

Virus

Mutations

Uncontrolled

cell growth

Proto-oncogenes

Tumor-suppressor genes

types of cancers based on etiologic agent
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--->melanomas
    • Highly tumorigenic
slide8

Chemical-induced tumors

e.g. methylcholanthrene

types of cancer based on the tissue affected
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
evidence for the role of immune system in tumor rejection
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)
antigens expressed on tumor cells
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)

tumor associated developmental ags
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
other tumor associated antigens
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
slide14

Inbred:

repeated brother-sister

matings

Tumor Growth

Syngeneic

(accepted)

Mouse

Outbred:

normal

population

Allogeneic

(rejected)

Across Species

Rat

Xenogeneic

(rejected)

how does a tumor escape immune surveillance

Tumor

How does a tumor escape immune surveillance?
  • Generation of Regulatory cells (CD4+CD25+ 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

slide16

Macrophage/

Dendritic cell

(Ag presenting

Cell)

tumor Ag

tumor

  • Failure to process and present tumor Ag.

B cell

MHC Class II

T helper (Th) cell

MHC Class I

Cytotoxic T lymphocyte (CTL)

tumor

tumor

slide17

tumor

Class I MHC

B7

CD28

tumor Ag

CTL

  • 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

slide18
Downregulation of MHC expression on tumor cell (CTL resistant but NK sensitive)

NK cell

Tumor

cell

tumor escape mechanisms
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.

slide20

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
immunotherapy
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
slide22

Normal

Mf

Tumor

Tumor

lysis

Activated

Mf

  • Nonspecific:
    • BCG (Bacillus Calmette-Guerin) Mycobacteria - melanoma, bladder carcinoma
slide23

IL-2R

Anti-IL-2R

IL-2

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)

monoclonal abs used in immunotherapy
Monoclonal Abs used in Immunotherapy
  • Unlabelled Ab: e.g. Anti-CD20 Ab in non-Hodgkin’s 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

slide25

Tumor

Ricin

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

adoptive immunotherapy

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

1 use of lak cells il 2 to treat cancer
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

2 use of tumor infiltrating lymphocytes il 2 to treat cancer
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

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

Cl II

Cl I

slide32
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
cytokine therapy

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

slide34

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)

gene therapy
Gene therapy

Introduce cytokine genes for IL-2, IL-4, IL-12, IFN-g orGM-CSF into tumor cells.

IL-2

GM-CSF

T cell

tumor

Mf

summary
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.
reading
Reading

Immunology

By Male, Brostoff, Roth and Roitt

7th Edition

Pages 401-419