The document discusses cancer and the immune system. It provides an overview of how tumors form and avoid detection by the immune system. It describes tumor antigens and how cancers evade the immune response through various mechanisms like reducing MHC molecules and releasing immunosuppressive cytokines. The document concludes by outlining different approaches to cancer immunotherapy, including enhancing co-stimulatory signals, cytokine therapy, monoclonal antibodies, and cancer vaccines.

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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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 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

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. What can go wrong?
 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 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

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-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)

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!