CANCER immunology and importance of oncogene

Cancer

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

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4. Cancer and the
Immune System

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

6. Metastasis
22.1

7. Types of Cancers
carcinoma: endodermal/ectodermal tissue
leukemia/lymphoma: hematopoeitic stem cells
sarcoma: mesodermal connective 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 G
o
confluent monolayer CHECKPOINT FAILURE
contact inhibition

9. Malignant Transformation
are like in vitrocancers
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

11. Oncogenes…
oncogene: “cancer
gene”; often found in
viral genomes
proto-oncogene:
cellular counterpart
which can be turned
into an oncogene

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. Whatcangowrong?
chromosomal translocations
tandem repeats: HSRs
mutations in proto-oncogenes
viral integration
growth factors and their receptors

14. Induction of Cancer
Fig. 22.2

15. Induction of Cancer

16. Lets Visualize!
http://science.education.nih.gov/supplem
ents/nih1/cancer/activities/activity2_anim
ations.htm

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)

18. Tumor Antigens
TSTAs
Tumor Specific Transplantation Antigen
TATAs
Tumor Associated Transplantation Antigen

19. TSTAs
Unique to tumor cells
DO NOToccur 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
Virallyinduced 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 ENHANCEit.
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

30. Conniving Cancer cont.
Reduction in
Class I MHC
Molecules

31. And the final blow…
Lack of Co-
Stimulatory
Signal

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-γalso 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)

43. Monoclonal Antibodies
• Anti-idiotype
• Growth Factors
-HER2
• Immunotoxins

45. Cancer Vaccines
• Genetic
Biochemical

46. HPV
Human Papilloma Virus
E6
E7

47. From Normal to Abnormal:

48. For more info
HPV
Cancer Vaccines

49. This Day Has
Been Brought to
you By the
Letter…
C
C is for Cancer!