Download Cancer and the Immune System

Cancer and the
Immune System
Immunology
Chapter 22
April 22, 2003
Amar Bhatt
Shirley Masand
Jaime Warmkessel
A Look Ahead
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Tumors and Metastasis
Oncogenes and Cancer Induction
Tumor Antigens
Tumors and the Immune Response
Immunotherapy
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Cancer and the
Immune System
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
Metastasis
22.1
Types of Cancers
carcinoma: endodermal/ectodermal tissue
leukemia/lymphoma: hematopoeitic stem cells
sarcoma: mesodermal connective tissues
What makes cancer
“cancer”?
1. decreased requirements for growth
factors and serum
2. are no longer anchorage dependent
3. grow independently of density
normal cells:
eventually enter Go
confluent monolayer
contact inhibition
CHECKPOINT FAILURE
Malignant
Transformation
 are like in vitro cancers
 two phases
1. initiation (changes in genome)
2. promotion (proliferation)
Malignant
Transformation

chemical and physical carcinogens

virally induced transformation

cultured tumors: good models for study

cancer cells are basically immortal
Oncogenes…
oncogene: “cancer
gene”; often found in
viral genomes
proto-oncogene:
cellular counterpart
which can be turned
into an oncogene
What can go right?
 induction of cellular
proliferation
 inhibition of cellular
proliferation, a.k.a. tumorsuppressor genes
 regulation of programmed
cell death
What can go wrong?





chromosomal translocations
tandem repeats: HSRs
mutations in proto-oncogenes
viral integration
growth factors and their receptors
Induction of Cancer
Fig. 22.2
Induction of Cancer
Lets Visualize!
 http://science.education.nih.gov/supplem
ents/nih1/cancer/activities/activity2_anim
ations.htm
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
 TSTAs
 Tumor Specific Transplantation Antigen
 TATAs
 Tumor Associated Transplantation Antigen
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
•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
 Express tumor antigens shared by all tumors induced
by the same virus
 Burkitt’s Lymphoma
 Epstein Barr
 HPV
Fig 22.9
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
 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 have the same
antigens for each tumor caused by that
virus.
 HPV
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?

You need three things:
1. “See” the cancer

Ternary complex and costimulation by B7
2. Activate lymphocytes

Release IL-2, IFN-gamma, and TNF-alpha
3. 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
But if the body has all
these defenses, why do
so many people still have
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
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
-
+
-
Effect
Source: Chouaib et al 1997
Conniving Cancer cont.
 Reduction in
Class I MHC
Molecules
And the final blow…
 Lack of CoStimulatory
Signal
Cancer Immunotherapy
 Manipulation of Co-Stimulatory
Signal
 Enhancement of APC Activity
 Cytokine Therapy
 Monoclonal Antibodies
 Cancer Vaccines
Manipulation of CoStimulatory 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 CoStimulatory Signal Cont.
 Basis for Vaccine
 Prevent metastasis after surgical removal or
primary melanoma in human patients
Enhancement of APC
Activity
 GM-CSF (Granulocyte-macrophage colonystimulating factor)
remember: CSFs are cytokines that induce the
formation of distinct hematopoietic cell lines
 Fig 22.11b
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.
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 Cont.
II.
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 Cont.
III.
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.
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 lymphocytes (TILs)
Monoclonal Antibodies
• Anti-idiotype
• Growth Factors
-HER2
• Immunotoxins
Cancer Vaccines
• Genetic
 Biochemical
HPV
Human Papilloma Virus
 E6
 E7
From Normal to Abnormal:
For more info
 HPV
 Cancer Vaccines
This Day Has
Been Brought to
you By the
Letter…
C
C is for Cancer!