1. Tumor immunology Immune erosion
Expected life-span yr
Cancer/ Infection/
Neuronal disorder Development

2. 十大癌症在台灣 (2005):
1. 肺癌
2. 肝癌
3. 結腸直腸癌
4. 女性乳癌
5. 胃癌
6. 口腔癌
7. 子宮頸癌
8. 攝護腺癌
9. 食道癌
10. 胰臟癌

3. Evidence for active host defense against cancer
80 years of immunotherapy. (Currie GA, 1972, Br. J. Cancer 26: 141)
A critique of the evidence for active host defense against cancer, based on personal studies of 27 murine tumors of spontaneous origin. (Hewitt HB, et al. 1976, Br. J. Cancer 33:241)

4. Anti-tumor immunity Circulating tumor antibodies
Circumvent evidence
Circulating tumor antibodies
Tumor infiltrating lymphocytes: CTL expansion and autologous tumor lysis.
MHC-I down-regulation

5. A fight between immune cells and cancer
But, sometimes we lose

6. The great escape: immune evasion versus tumor progression

7. Immune selection in the development of cancer: no two tumors are alike
Fey MF & Tobler A 1996
Initiation, proliferation diversification
Microevolution, selection of immune resistance
Immune escape and unchecked proliferation

8. Use of tumor cell lines Commonly derived from advanced tumors
Retain the genetic instability and lose the ability of adaptations
introduced in large numbers (more than 106 cells)

9. Tumor formation of Ras-over-expression cells in BALB/c
A dynamic process
Tumor formation of Ras-over-expression cells in BALB/c

10. Mechanisms of tumor escape
Resistance to killing
Antigen-specific mechanisms (Treg?)
Down-regulation of the class I presentation pathway
Global mechanisms

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

12. Resistance to killing Cytotoxic T cells Innate immunity
Defective Fas pathway
Resistance to Granzyme B
Innate immunity
Fas-L and Neutrophil

13. Fas signal

14. Loss sensitivity to Fas-mediated apoptosis
FLICE-like inhibitory proteins
Bcl-2, Bcl-XL
defected sphingomyelinase activation (ceramide)
decoy receptor 3 (DcR3), soluble Fas

15. Fas-L+-melanoma cells are relatively resistant to killing of neutrophils
B16F10
Chen YL, et al J. Immunol. 171:

16. Antigen-specific mechanisms
Tumor antigen-loss variants
Loss of the melanoma tumor-associated antigen in patients with recurrent metastatic melanoma (J Clin Invest 1996, 98:1633)
Tolerance
B cell tumors expressing class II induced a rapid tolerance of cognate CD4 T cell carrying a transgenic TCR. (PNAS, 1998, 95:1178)

17. Tumor associated antigens
Tumor-specific shared antigens: restricted in expression to tumors and immune privilege sites.
Tissue-specific differentiation antigens: tyrosinase. (melanoma)
Tumor-specific antigens: mutated, tranlocated genes.
Ubiquitous antigens with over-expression in tumors.
Rosenberg SA. 1999, Immunity 10:281

18. HLA class I molecules Antigen presentation for T cells
Inhibitory signals for NK cells
Tumor escape from T cells
Immunotherapy with peptide

19. Down regulation of the MHC class presentation pathway
Downregulation of MHC class I expression is frequently seen in human tumors.
Loss of MHC-I as a mechanism for tumor escape from CTL-mediated elimination (longitudinal study of melanoma patients)
Five major HLA altered phenotypes found in tumor tissues (Human Immunol. 2000, 61:65)

20. The five altered phenotypes
Normal A1A2B8B35Cw7Cw4
1. Total loss
2. Haplotype loss A1B8Cw7
3. Locus loss A1A2B8B35
4. Allelic loss A2B8B35Cw7Cw4
5. Compound
phenotype A1
(Human Immunol. 2000, 61:65)

21. Global Mechanisms TGF-beta IL-10 Growth in immune privilege sites
Mucin production: interfering intercellular adhesion
Fas-L? (Fas counterattack)
Extracellular matrix?

22. TGF-b signaling in tumor signaling and cancer progression

23. IL-10 (Th3 or Treg)
Tumors or other cells in environments

24. Mediation of Enhanced Transcription of the IL-10 Gene in T Cells, Upon Contact with Human Glioma Cells, by Fas Signaling Through a Protein Kinase A-Independent Pathway1
J Immunol, 2003, 171: 3947–3954.
Jurkat and Molt-4 cells were cultured alone (lane 1) or in the presence of U118(V), U118(R), U373(V), or U373(R) (lanes 2, 3, 4, and 5, respectively) for 24 h.

25. How can tumor cells highjack immune cells?
transwell
J Immunol. In revision, 2007

26. Immune therapy Recombinant and synthetic vaccination
Cytokine treatments (IL-2; GM-CSF; IFN)
Cellular therapy with tumor-specific CTL
Engineered macrophages
Antigen-pulsed macrophages or dendritic cells

27. Peptide epitopes for melanoma
Nicholaas P, et al. 1999, Curr Opin Oncol 11:50

28. Nair SK, et al. 1998, Nature Biotech 16:364
DC generated from the PBMC of healthy individuals or from cancer patients transfected with CEA mRNA stimulate a potent CD8+ CTL response in vitro. RNA encoding a chimeric CEA/LAMP-1 lysosomal targeting signal enhances the induction of CEA-specific CD4+ T cells in vivo.

29. A FasL mystery Tissue dependant Reverse signaling?
Other than death-triggering

30. In vivo consequences of Fas-L expression by tumors (using over-expression system)
Enhanced rejection
Delayed rejection
CT26#
B16-F10
Renca, MH134, L5178Y, B16-BL6, CT26*
Note: *:syngenic, nude, SCID #: allogenic, lpr
Ref: Lejeune FJ et al., 1998, Curr. Op. Immunol.

31. Distinct structure of tumor mass
Control
Glioma in Nude mice
May be Fas-L associated?
Why TIL in particular sites?
Penetration of tumor by immune cells
Fas-LR

32. B16-F10 (melanoma) in B6 mice
Control Fas-LRibozyme

33. Depletion of CD4, CD8 T cells and PMNs affected subcutaneous tumor formation
Vector controls
Fas-L-ribozyme

34. Granulocytes mediates the Fas-L-associated apoptosis during lung metastasis of melanoma that determines the metastatic behavior (B16F10 in C57BL/6)
Br J Cancer, 87: 359 (2002)

35. Depletion of CD4, CD8 T cells and PMNs affected lung metastasis44 41
357 10 95
154
Vector controls
Fas-Lribozyme
What happened here?

36. Tumor What will happen when Fas-stimulated immune cells resist to die?
Tissue environment ?
Tumor
Fas-L
Immune cells
Fas
Cytokines ?

37. Regulatory T cells: the third man
Shimon Sakaguchi (2000) Regulatory T Cells Key Controllers of Immunologic Self-Tolerance Cell 101:

38. Alternative paradigm
A tumor is a local growth of abnormal tissue consisting of genetic-altered transformed cells and a number of other cell types and connective tissue components characteristic of each tumor type.
No host, as a tissue, no fighting.
Seljelid R et al 1999, Anticancer Res 19:4809

39. Complex three-way interactions between tumor cells, their microenvironment and the immune system.
Nature Med.1999,

40. Tumor Stroma Fibroblasts Macrophages
lymphoid cells (T, B, granulocytes, NK cells)
mast cells
endothelium
intercellular substance; extracellular matrix

41. A B C A. tumor as abnormal growth of transformed cells.
Black squares: tumor cells; Round: lymphocytes;
Oval: macrophages; small circles: mast cells A
A. tumor as abnormal growth of transformed cells.
B. Tumor as malignant tissue.
C. Tumor hijacks macrophage to direct growth. B C
Seljelid R. 1997, Scan J Immunol 46:437