Transcript Advance in tumor immunology

Tumor immunology
Immune erosion
Expected life-span
100
60
Cancer/
Neuronal disorder
10
0yr
Infection/
Development
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
Evidence for active host
defense against cancer
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80 years of immunotherapy. (Currie GA,
1972, Br. J. Cancer 26: 141)
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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)
Anti-tumor immunity
Circumvent evidence
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Circulating tumor
antibodies
Tumor infiltrating
lymphocytes: CTL expansion
and autologous tumor lysis.
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MHC-I down-regulation
A fight between immune cells and cancer
But, sometimes we lose
The great escape:
immune evasion
versus tumor
progression
Immune selection in the development
of cancer: no two tumors are alike
Fey MF & Tobler A 1996
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Initiation,
 Microevolution,
proliferation
selection of
diversification immune
resistance
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Immune escape
and unchecked
proliferation
Use of tumor cell lines
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Commonly derived from advanced
tumors
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Retain the genetic instability and lose
the ability of adaptations
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introduced in large numbers (more
than 106 cells)
A dynamic process
Tumor formation of Ras-over-expression cells in
BALB/c
Mechanisms of tumor escape
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Resistance to killing
Antigen-specific
mechanisms (Treg?)
Down-regulation of
the class I
presentation
pathway
Global mechanisms
Tumor and activated T cells
Two major pathways for TCL: Fas-mediated and perforrin-mediated
Resistance to killing
Cytotoxic T cells
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Defective Fas pathway
Resistance to Granzyme B
Innate immunity
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Fas-L and Neutrophil
Fas signal
Loss sensitivity to Fas-mediated
apoptosis
 FLICE-like
inhibitory proteins
 Bcl-2, Bcl-XL
 defected sphingomyelinase
activation (ceramide)
 decoy receptor 3 (DcR3), soluble
Fas
Fas-L+-melanoma cells are relatively
resistant to killing of neutrophils
B16F10
Chen YL, et al J. Immunol. 171:1183-1192.
Antigen-specific mechanisms
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Tumor antigen-loss
variants
Loss of the melanoma tumor-associated
antigen in patients with recurrent metastatic
melanoma (J Clin Invest 1996, 98:1633)
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Tolerance
B cell tumors expressing class II induced a rapid
tolerance of cognate CD4 T cell carrying a
transgenic TCR. (PNAS, 1998, 95:1178)
Tumor associated antigens
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Tumor-specific shared antigens: restricted
in expression to tumors and immune privilege sites.
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Tissue-specific differentiation antigens:
tyrosinase. (melanoma)
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Tumor-specific antigens: mutated,
tranlocated genes.
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Ubiquitous antigens with overexpression in tumors.
Rosenberg SA. 1999, Immunity 10:281
HLA class I molecules
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Antigen presentation
for T cells
Inhibitory signals for
NK cells
Tumor escape from T cells
Immunotherapy with
peptide
Down regulation of the MHC
class presentation pathway
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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)
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Five major HLA altered phenotypes found in
tumor tissues (Human Immunol. 2000, 61:65)
The five altered phenotypes
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Normal
1. Total loss
2. Haplotype loss
3. Locus loss
4. Allelic loss
5. Compound
phenotype
A1A2B8B35Cw7Cw4
A1B8Cw7
A1A2B8B35
A2B8B35Cw7Cw4
A1
(Human Immunol. 2000, 61:65)
Global Mechanisms
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TGF-beta
IL-10
Growth in immune privilege
sites
Mucin production: interfering
intercellular adhesion
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Fas-L? (Fas counterattack)
Extracellular matrix?
TGF-b signaling in tumor signaling and
cancer progression
IL-10 (Th3 or
Treg)
Tumors or other cells in environments
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.
How can tumor cells highjack
immune cells?
Jurkat T cells
transwell
70.0
60.0
50.9
48.8
Apoptosis (%)
50.0
40.5
40.0
30.0
26.5
25.4
30.0
25.4
20.0
10.0
6.4
5.5
5.3
0.0
di
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18
U-1
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(up
18
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J Immunol. In revision, 2007
Immune therapy
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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
Peptide epitopes for melanoma
Nicholaas P, et al. 1999, Curr Opin Oncol 11:50
Nair SK, et al. 1998, Nature Biotech 16:364
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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.
A FasL mystery
1. Tissue dependant
2. Reverse signaling?
3. Other than death-triggering
In vivo consequences of Fas-L
expression by tumors
(using over-expression system)
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Enhanced
rejection
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Renca, MH134,
L5178Y, B16BL6, CT26*
Note: *:syngenic, nude, SCID
Delayed
rejection
CT26#
B16-F10
#:
allogenic, lpr
Ref: Lejeune FJ et al., 1998, Curr. Op. Immunol.
Distinct structure of tumor mass
Control
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Glioma in Nude
mice
May be Fas-L
associated?
Why TIL in
Fas-LR
particular sites?
Penetration of
tumor by immune
cells
B16-F10 (melanoma) in B6 mice
Control
Fas-LRibozyme
Depletion of CD4, CD8 T cells and PMNs
affected subcutaneous tumor formation
Vector controls
Fas-L-ribozyme
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)
Depletion of CD4, CD8 T cells and PMNs
affected lung metastasis
44
10
41
Vector controls
What happened here?
357
95
154
Fas-Lribozyme
What will happen when Fas-stimulated
immune cells resist to die?
Tissue environment ?
Tumor
Fas-L
Fas
Cytokines ?
Immune
cells
Regulatory T cells: the third man
Shimon Sakaguchi (2000) Regulatory T Cells Key Controllers of
Immunologic Self-Tolerance Cell 101: 455-458
Alternative paradigm
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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
Complex three-way interactions between tumor
cells, their microenvironment and the immune
system.
Nature Med.1999,874-875
Tumor Stroma
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Fibroblasts
Macrophages
lymphoid cells (T, B, granulocytes, NK
cells)
mast cells
endothelium
intercellular substance; extracellular
matrix
Black squares: tumor cells; Round: lymphocytes;
Oval: macrophages; small circles: mast cells
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A. tumor as abnormal
growth of transformed
cells.
B. Tumor as malignant
tissue.
C. Tumor hijacks
macrophage to direct
growth.
A
B
C
Seljelid R. 1997, Scan J Immunol 46:437