1. Objectives Introduction Ags expressed by cancer cells
Nature of immune response
How cancer evades immune system
Immunotherapy

2. Cancer Introduction Uncontrolled growth produces a tumor or neoplasm.
A tumor that grows indefinitely and often spreads (metastasis) is called malignant--also called cancer.
A tumor that is not capable of indefinite growth----benign.
Malignant---kills host.
Benign---does not kill host.

3. Molecular Basis of Cancer
Radiation
Chemical (Carcinogen)
Virus
Mutations
Uncontrolled
cell growth
Proto-oncogenes
Tumor-suppressor genes

4. Types of cancers based on etiologic agent
Chemically-induced tumors
Each tumor induced by a carcinogen (e.g. benzopyrene) injected at various sites expresses a unique Ag.
Thus difficult to develop vaccine.
Virus-induced tumors
Tumors induced by same virus express same tumor Ag.
Induce a strong immune response.
Human Papilloma Virus (HPV) induced cervical cancer
UV-induced tumors
UV radiation--->melanomas
Highly tumorigenic

5. Evidence for the role of immune system in tumor rejection
Infiltration of tumors by lymphocytes and macrophages
Regression of metastases after removal of primary tumor
Regression after chemotherapy
Lymphocyte proliferation in draining lymph nodes
Higher incidence of cancer after immunosuppression/immunodeficiency (AIDS, neonates, aged, transplant patients)

6. Antigens expressed on tumor cells
Major Histocompatability
Complex antigens
TSTA
Tumor-specific
transplantation Ag
TATA
Tumor-associated
transplantation Ag
TSTA: unique to a tumor
Play an important role in tumor rejection.
TATA: shared by normal and tumor cells
Tumor-associated developmental Ag (TADA)
Tumor-associated viral Ag (TAVA)

7. Tumor-Associated Developmental Ags
Found on cancer cells and on fetal cells.
Do not trigger anti-tumor immunity.
Used in diagnosis.
Alpha-fetoprotein(AFP) Cancers of liver
Carcinoembryonic Ag (CEA) colorectal cancer

8. Other Tumor associated antigens
Differentiation Ags: B cells produce surface Ig. B cell tumors have sIg
Overexpression of Ag on tumors compared to normal cells e.g. In breast cancer, HER2/neu
Ags expressed on male germ cells and melanoma e.g. MAGE-1

9. Tumor Antigen

10. Antitumor Effector Mechanisms
Immune surveillance : Recognize and destroy clones of transformed cells before they grow into tumors and to kill tumors after they are formed.
NK cell
Cytotoxic T-cell
Humoral
Mechanisms
Macrophage

11. Tumor Immunity

12. Tumor and activated T cells
Two major pathways for TCL: Fas-mediated and perforrin-mediated

13. How does a tumor escape immune surveillance?
Generation of Regulatory cells (CD4+CD25+ FoxP3+ T cells) or Myeloid-derived suppressor cells(Gr-1+ CD11b+)
Secrete immunosuppressive molecules Ex: Transforming growth factor beta (TGF-b), interleukin-10 (IL-10), etc.
T regs
CTL
Tumor
MDSC
IL-10, etc

14. Failure to process and present tumor Ag.
Macrophage
tumor Ag
tumor
B cell
MHC Class II
T helper (Th) cell
MHC Class I
Cytotoxic T lymphocyte (CTL)
tumor
tumor

15. Tumors may fail to express costimulatory
molecules involved in T cell activation.
tumor
CTL
tumor Ag
Class I MHC B7
CD28
Tumors escape the action of CTL by not expressing B7 which provides 2nd signal involved in T cell activation

16. Downregulation of MHC expression on tumor cell (CTL resistant but NK sensitive)
NK cell
Tumor
cell

17. Tumor escape mechanisms:
Fas
FasL
Tumor
CTL
FasL
Fas
Tumor
CTL
When tumor cells express Fas Ligand,
they can kill Fas+ T cells, thereby escaping
immune destruction.

18. Traditional approaches to treat cancer
Surgery Radiation Chemotherapy
Localized tumors Metastastic tumors Affects proliferating cells
(bone marrow, etc.)
Radiation/Drug-resistant tumors
Novel Mode: Immunotherapy

19. Immunotherapy
Active Immunization: The host actively elicits an immune response.
Specific
Vaccination with viral Ags: e.g.
Hepatitis B virus
Human Papilloma virus (HPV) - Gardasil

20. Nonspecific:
BCG (Bacillus Calmette-Guerin) Mycobacteria - melanoma, bladder carcinoma
Normal Mf
Tumor
Activated
lysis

21. Passive Immunization: Preformed Abs or immune cells transferred
Specific: Ab Therapy
Abs against growth factor receptor e.g. IL-2R in HTLV-1 induced Adult T cell leukemia
Abs specific for oncogene product e.g. Abs against HER2/neu (Herceptin or trastuzumab)
IL-2R
IL-2
Anti-IL-2R

22. Anti-tumor Abs coupled to toxin, radioisotopes, drugs or enzymes:
Immunotoxins:
Ricin A/diphtheria/Pseudomonas toxin coupled to Abs. e.g. antiCD20-Pseudomonas toxin in B cell leukemia
Internalized toxin inhibits protein synthesis.
Tumor
Ricin

23. Cytokine Therapy Inject cytokines.
1. Interleukin -2 (IL-2) high dose - Alone or with cells
Melanoma and renal cell carcinoma
Activates NK and CTL
Toxic - fever, edema, shock
2. Tumor necrosis factor (TNF-a) -Carcinoma

24. SUMMARY Tumors should express TSTA.
Th cells and CTL are important in tumor rejection.
NK cells and macrophages also play an important role.
Tumors evade immune system in a number of ways.
Immunotherapy is promising.