Advimmunology by liaoxiuli

VIEWS: 10 PAGES: 41

									 Tumor immunology
            Immune erosion
                Expected life-span
100              60               10        0yr
      Cancer/                       Infection/
      Neuronal disorder          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

   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)
Anti-tumor immunity
Circumvent evidence
       Circulating tumor
        antibodies
       Tumor infiltrating
        lymphocytes: CTL expansion
        and autologous tumor lysis.

       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




    Initiation,     Microevolution,      Immune escape
     proliferation    selection of          and unchecked
     diversification immune                 proliferation
                      resistance
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)
       A dynamic process




Tumor formation of Ras-over-expression cells in
BALB/c
Mechanisms of tumor escape

   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
        Defective Fas pathway
        Resistance to Granzyme B


Innate immunity
        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
   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)
    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
HLA class I molecules
   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

   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)
     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)
    Global Mechanisms

   TGF-beta
   IL-10
   Growth in immune privilege
    sites
   Mucin production: interfering
    intercellular adhesion
   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


                70.0                                                                                                                                                     transwell

                60.0
                                                                                                                                                                                               50.9
                                                                                                                                      48.8
                50.0
                                      40.5
Apoptosis (%)




                40.0                                                                                                                                                                                                    30.0
                                                                          25.4                              26.5                                                  25.4
                30.0

                20.0

                10.0         5.3                      5.5                                 6.4

                 0.0
                                                                                                                                         )                           )                                                     )
                          diu
                              m      -11         18   V
                                                                        H-1
                                                                            1
                                                                                     18   R
                                                                                                          H- 1
                                                                                                              1
                                                                                                                                     per                           om                         er )                     t om
                       me          CH        U-1                      +C         U-1                    +C                       (up                           o tt                    (   upp                      bot
                                                                18V                                   8R                   -11                             1 (b                   - 11                         1(
                                                            U-1                                 U-1
                                                                                                    1
                                                                                                                         CH                            H-1                      CH                         H- 1
                                                                                                                       V+                        V   +C                       R+                         +C
                                                                                                                  18                        18                           18                           18R
                                                                                                              U-1                       U-1                          U-1                        U-1




                                                                                                   J Immunol. In revision, 2007
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
Peptide epitopes for melanoma




               Nicholaas P, et al. 1999, Curr Opin Oncol 11:50
             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.
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)


   Enhanced                           Delayed
    rejection                           rejection

    Renca, MH134,                        CT26#
    L5178Y, B16-                         B16-F10
    BL6, CT26*
     Note: *:syngenic, nude, SCID          #:   allogenic, lpr
        Ref: Lejeune FJ et al., 1998, Curr. Op. Immunol.
     Distinct structure of tumor mass
                      Control
   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               41     357
        10                     95
                                        154




     Vector controls          Fas-Lribozyme
  What happened here?
What will happen when Fas-stimulated
immune cells resist to die?


              Tissue environment ?


    Tumor     Fas-L
                              Immune
                              cells
                      Fas


                Cytokines ?
  Regulatory T cells: the third man




Shimon Sakaguchi (2000) Regulatory T Cells Key Controllers of
Immunologic Self-Tolerance Cell 101: 455-458
    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
Complex three-way interactions between tumor
cells, their microenvironment and the immune
system.




                              Nature Med.1999,874-875
Tumor Stroma

   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

                                  A
   A. tumor as abnormal
    growth of transformed
    cells.

   B. Tumor as malignant         B
    tissue.

   C. Tumor hijacks
    macrophage to direct
    growth.
                                  C


                                  Seljelid R. 1997, Scan J Immunol 46:437

								
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