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Cancer and the Immune System. Amar Bhatt Shirley Masand Jaime Warmkessel. Immunology Chapter 22 April 22, 2003. A Look Ahead. Tumors and Metastasis Oncogenes and Cancer Induction Tumor Antigens Tumors and the Immune Response Immunotherapy. FATAL SYSTEM ERROR.

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cancer and the immune system

Cancer and theImmune System

Amar Bhatt

Shirley Masand

Jaime Warmkessel

Immunology

Chapter 22

April 22, 2003

a look ahead
A Look Ahead
  • Tumors and Metastasis
  • Oncogenes and Cancer Induction
  • Tumor Antigens
  • Tumors and the Immune Response
  • Immunotherapy
fatal system error
FATAL SYSTEM ERROR

An exception error has occurred at AP222003C22. A virus has been detected. Quarantine has failed but the virus has been identified. Press the Any key to return to windows in safe sesame mode.

cancer
Cancer

“altered self-cells that have escaped normal growth regulation mechanisms”

neoplasm: tumor

benign vs. malignant

metastasis: spreading of cancerous cells via blood or lymph to various tissues

types of cancers
Types of Cancers

carcinoma: endodermal/ectodermal tissue

leukemia/lymphoma: hematopoeitic stem cells

sarcoma: mesodermal connective tissues

what makes cancer cancer
What makes cancer “cancer”?
  • decreased requirements for growth factors and serum
  • are no longer anchorage dependent
  • grow independently of density

normal cells:

eventually enter Go

confluent monolayer CHECKPOINT FAILURE

contact inhibition

malignant transformation
Malignant Transformation
  • are like in vitro cancers
  • two phases
    • initiation (changes in genome)
    • promotion (proliferation)
malignant transformation10
Malignant Transformation
  • chemical and physical carcinogens
  • virally induced transformation
  • cultured tumors: good models for study
  • cancer cells are basically immortal
oncogenes
Oncogenes…

oncogene: “cancer gene”; often found in viral genomes

proto-oncogene: cellular counterpart which can be turned into an oncogene

what can go right
What can go right?
  • induction of cellular proliferation
  • inhibition of cellular proliferation, a.k.a. tumor-suppressor genes
  • regulation of programmed cell death
what can go wrong
Whatcangowrong?
  • chromosomal translocations
  • tandem repeats: HSRs
  • mutations in proto-oncogenes
  • viral integration
  • growth factors and their receptors
lets visualize
Lets Visualize!
  • http://science.education.nih.gov/supplements/nih1/cancer/activities/activity2_animations.htm
tumors of the immune system
Tumors of the Immune System
  • Lymphomas
    • Solid tumors w/in lymphoid tissue (bone marrow, lymph nodes, thymus)
    • Hodgkin’s & non-Hodgkin’s
      • http://www.lymphomainfo.net/
  • Leukemias
    • Proliferate as single cells
    • Acute or Chronic depending on the progression of disease
      • Acute- appear suddenly and progress rapidly; arise is less mature cells (ie ALL, AML)
      • Chronic- much less aggressive and develop slowly; mature cells (ie CLL and CML)
tumor antigens
Tumor Antigens
  • TSTAs
    • Tumor Specific Transplantation Antigen
  • TATAs
    • Tumor Associated Transplantation Antigen
tstas
TSTAs
  • Unique to tumor cells
  • DO NOT occur on normal cells in the body
  • Novel proteins created my mutation presented on class I MHC
  • Can either be chemically/physically induced or virally induced tumor antigens
chemically physically induced
Chemically/Physically Induced
  • Specific Immunologic Response that can
  • Protect against later challenge by live cells
  • Of the same line but not other tumor-line
  • Cells.
  • Methylcholanthrene / UV light

Fig 22.7

virally induced
Virally Induced
  • Express tumor antigens shared by all tumors induced by the same virus
  • Burkitt’s Lymphoma
    • Epstein Barr
  • HPV

Fig 22.9

tatas
TATAs
  • NOT unique to tumor cells
  • DO occur on normal cells in the body
  • So where’s the problem?
    • Fetal/adult presence
    • Concentration of Growth Factors and Growth Factor Receptors
tatas cont d
TATAs cont’d
  • Oncofetal Tumor Antigens (AFP & CEA)
    • Normally appear in fetus before immunocompetence
    • Later recognized as non-self
  • Oncogene Proteins
  • Human Melanomas
virally induced tumors
Virally Induced Tumors
  • Virally induced tumors have the same antigens for each tumor caused by that virus.
  • HPV
immune response to tumors
Immune Response to Tumors
  • Mostly a cell-mediated response
  • NK Cells
    • Not MHC restricted
    • Fc receptor binds to antibody coated tumor cell  ADCC
    • Chedieak-Higashi syndrome
  • Macrophages
    • Not MHC restricted
    • Elicits ADCC
    • TNF-alpha
  • Immune Surveillance Theory
so you have a tumor cell now what
So, you have a tumor cell.Now what?
  • You need three things:
    • “See” the cancer
      • Ternary complex and costimulation by B7
    • Activate lymphocytes
      • Release IL-2, IFN-gamma, and TNF-alpha
    • Cancer cells must be susceptible to killing
      • CTL lysis, macrophages, NK cells

Info From:

http://www.brown.edu/Courses/Bio_160/Projects1999/cancer/imevstca.html#Introduction

conniving cancer
Conniving Cancer.
  • Bad antibodies?
    • Some antibodies do not protect against tumor growth, but also ENHANCE it.
    • Release of immunosuppressive cytokines
      • transforming growth factor-beta (TGF-beta), interleukin-10 (IL-10) and vascular endothelial growth factor (VEGF)
  • Hide and go Seeking Antigen
    • Antigens actually seem to “hide” in the presence of antibody
    • Also, some cancer cells completely shed themselves of the antigen
slide29

Effect

TGF-beta

IL-10

VEGF

Inhibition of T-cell growth

+

-

+

Inhibition of CTL differentiation

+

+

+

Inhibition of cytokine production

+

+

-

Induction of T-cell anergy

+

-

-

Downregulation of cytotoxic potential

+

+

-

Inhibition of antigen presentation

+

+

-

Shift in the Th1-Th2 balance towards Th2

+

+

-

Downregulation of adhesion/costimulatory molecules

+

+

-

Resistance to CTL-mediated lysis

-

+

-

Source: Chouaib et al 1997

conniving cancer cont
Conniving Cancer cont.
  • Reduction in Class I MHC Molecules
and the final blow
And the final blow…
  • Lack of Co- Stimulatory Signal
cancer immunotherapy
Cancer Immunotherapy
  • Manipulation of Co-Stimulatory Signal
  • Enhancement of APC Activity
  • Cytokine Therapy
  • Monoclonal Antibodies
  • Cancer Vaccines
manipulation of co stimulatory signal
Manipulation of Co-Stimulatory Signal
  • Tumor immunity can be enhanced by providing the co-stimulatory signal necessary for activation of CTL precursors (CTL-Ps)
  • Fig. 22.11a
manipulation of co stimulatory signal cont
Manipulation of Co-Stimulatory Signal Cont.
  • Basis for Vaccine
    • Prevent metastasis after surgical removal or primary melanoma in human patients
enhancement of apc activity
Enhancement of APC Activity
  • GM-CSF (Granulocyte-macrophage colony-stimulating factor)

remember: CSFs are cytokines that induce the formation of distinct hematopoietic cell lines

  • Fig 22.11b
cytokine therapy
Cytokine Therapy
  • Use of recombinant cytokines (singly or in combination) to augment an immune response against cancer
    • Via isolation and cloning of various cytokine genes such as:
    • IFN-α, β, and γ
    • Interleukin 1, 2, 4, 5, and 12
    • GM-CSF and Tumor necrosis factor (TNF)
cytokine therapy cont
Cytokine Therapy Cont.

I. Interferons

• Most clinical trials involve IFN-α

• Has been shown to induce tumor regression in

hematologic malignancies i.e. leukemias,

lymphomas, melanomas and breast cancer

• All types of IFN increase MHC I expression

• IFN-γ also has also been shown to increase MHC

II expressionon macrophages and increase

activity of Tc cells, macrophages, and NKs

cytokine therapy cont40
Cytokine Therapy Cont.
  • Tumor Necrosis Factors

• Kills some tumor cells

• Reduces proliferation of tumor cells without

affecting normal cells

How?

• Hemorrhagic necrosis and regression, inhibits

tumor induced vascularization (angio-genesis)

by damaging vascular endothelium

cytokine therapy cont41
Cytokine Therapy Cont.
  • In Vitro-Activited LAK & TIL cells

A. Lymphocytes are activated against tumor

antigens in vitro

• Cultured with x-irradiated tumor cells in

presence of IL-2

• Generated lymphokine activated killer

cells (LAKs), which kill tumor cells

without affecting normal cells

in vitro activated lak and tif cells cont
In Vitro-Activated LAK and TIF cells Cont.

B. Tumors contain lymphocytes that have

infiltrated tumor and act in anti-tumor

response

• via biopsy, obtained cells and

expanded population in vitro with

• generated tumor-infiltrating lympho-

cytes (TILs)

monoclonal antibodies
Monoclonal Antibodies

• Anti-idiotype

• Growth Factors

-HER2

• Immunotoxins

cancer vaccines
Cancer Vaccines

• Genetic

  • Biochemical
slide46
HPV

Human Papilloma Virus

  • E6
  • E7
for more info
For more info
  • HPV
  • Cancer Vaccines