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CANCER3C (1).PPT
1. Cancer and the
Immune System
Amar Bhatt
Shirley Masand
Jaime Warmkessel
Immunology
Chapter 22
April 22, 2003
2. A Look Ahead
• Tumors and Metastasis
• Oncogenes and Cancer Induction
• Tumor Antigens
• Tumors and the Immune Response
• Immunotherapy
3. FATAL SYSTEM ERROR
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5. 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
8. 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 CHECKPOINT FAILURE
contact inhibition
9. Malignant Transformation
are like in vitro cancers
two phases
1.initiation (changes in genome)
2.promotion (proliferation)
10. Malignant Transformation
chemical and physical carcinogens
virally induced transformation
cultured tumors: good models for study
cancer cells are basically immortal
12. What can go right?
induction of cellular
proliferation
inhibition of cellular
proliferation, a.k.a. tumor-
suppressor genes
regulation of programmed
cell death
13. What can go wrong?
chromosomal translocations
tandem repeats: HSRs
mutations in proto-oncogenes
viral integration
growth factors and their receptors
17. 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)
19. 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
20. Chemically/Physically Induced
Fig 22.7
•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
21. Virally Induced
Express tumor antigens shared by all tumors induced
by the same virus
Burkitt’s Lymphoma
Epstein Barr
HPV
Fig 22.9
22. 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
23. TATAs cont’d
Oncofetal Tumor Antigens (AFP & CEA)
Normally appear in fetus before
immunocompetence
Later recognized as non-self
Oncogene Proteins
Human Melanomas
24. Virally Induced Tumors
Virally induced tumors have the same
antigens for each tumor caused by that
virus.
HPV
25. 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
26. 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
27. But if the body has all
these defenses, why do
so many people still have
cancer?
28. 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
29. 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
31. And the final blow…
Lack of Co-
Stimulatory
Signal
32.
33.
34. Cancer Immunotherapy
Manipulation of Co-Stimulatory
Signal
Enhancement of APC Activity
Cytokine Therapy
Monoclonal Antibodies
Cancer Vaccines
35. 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
36. Manipulation of Co-Stimulatory Signal Cont.
Basis for Vaccine
Prevent metastasis after surgical removal or
primary melanoma in human patients
37. 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
38. 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)
39. 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
40. 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
41. 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
42. 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)