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Karibaldi Triastara

Windy Juliandra
M. Arsyi
Components of the Immune
System

Nonspecific Specific

Humoral Cellular Humoral Cellular

complement,
macrophages, T cells; other
interferon, antibodies
neutrophils effectors cells
TNF etc.
 Spontaneous regression
 Regression of metastases after removal of
primary tumor
 Regression after chemotherapy
 Infiltration of tumors by lymphocytes and
macrophages
 Lymphocyte proliferation in draining lymph
nodes
 Higher incidence of cancer after
immunosuppression/immunodeficiency (AIDS,
neonates, aged, transplant patients)
•Immunosurveillance - the tumor-
suppressing role of the immune system.

•Immunostimulation - the tumor-


promoting role of the immune system.

•tumor and immune system interact:


mutual influence!
•1909 Paul Ehrlich :cancer occurs spontaneously in
vivo and that the immune system is able to both
recognize and protect against it .
•late 1950s Lewis Thomas : the theory of
immunosurveillance, which was subsequently
developed by Sir MacFarlane Burnet .
•immunosurveillance :physiologic function of the
immune system Cancerous cells foreign can
be constantly eliminated by immune surveillance.

Ichim, C.V. J Transl Med 3, 8 (2005).


• Increased incidence of virally-induced tumors in
Immunosuppressed patients

• Studies showing increase in de novo malignant


melanoma in organs transplant patients

• 25-fold increase in incidence of lung


carcinoma in cardiac transplant patients

• Reverse correlations between tumor infiltrating


lymphocytes and tumor survival

Dunn et al. Nature Reviews Immunology 6, 836–848


(2006)
• The proof of the principle that an
inappropriate type of immune response
will enhance tumor growth was
demonstrated in 1907 by Flexner and
Jobling, injection of dead autologous
tumor cells enhanced the growth of pre-
existing tumors.
Modern view: The concept of
immunosurveillance has been modified and is
now considered in three phases:
1. “Elimination phase” - recognition and
destruction of the tumor cells
2. “Equilibrium phase” – occurs if elimination
is not successful. tumor cells undergo
changes in a process called immunoediting.
3. “Escape phase”- tumor cells evolved
enough to grow unimpeded and form a
tumor
Mechanisms by which tumor escape immune defenses:

1) Reduced levels or absence of MHCI molecule on tumor so


that they can not be recognized by CTLs

2) Some tumors stop expressing the antigens


These tumors are called “antigen loss variants”

3) Production of immunosuppressive factors by tumor e.g.


transforming growth factor (TGF-β)

4) Tumor antigens may induce specific immunologic tolerance


Lack of
Neo-antigens

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Lack of
co-stimulatory
molecules

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Lack of
class I MHC

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Tumors secrete
Immunosuppressive
molecules

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Tumors shed their
neo-antigens

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4) B-cells :
- Tumor associated antigens stimulate production of specific antibodies
by host B-cells
- These specific antibodies bind together on tumor cell surface
leading to destruction of tumor through:
a- Antibody mediated-cytotoxicity :
kill
Cytotoxic T-cells IgG-coated tumor cells
b- Activation of macrophages
release
Sensitized T-cells macrophage activating factor
IgG-coated tumor cells macrophages activate

c- Activation of classical pathway of complement leading to


Lysis of tumor cells
Mechanisms by which tumor escape immune defenses:

1) Reduced levels or absence of MHCI molecule on tumor so


that they can not be recognized by CTLs

2) Some tumors stop expressing the antigens


These tumors are called “antigen loss variants”

3) Production of immunosuppressive factors by tumor e.g.


transforming growth factor (TGF-β)

4) Tumor antigens may induce specific immunologic tolerance


5) Tumor cells have an inherent defect in antigen processing
and presentation

6) Blocking of receptors on T-cells by specific antigen


antibodies complex (after shedding of tumor Ag) prevents
them from recognizing and attacking tumor cells

7) Antigens on the surface of tumors may be masked by sialic


acid-containing mucopolysaccharides

8) Immune suppression of the host as in transplant


patients who show a higher incidence of malignancy
* Tumor markers :

Tumor antigens
* They are either or
Tumor products
(enzymes and hormones)

* Tumor products are released in the serum of patients

* They are used to confirm diagnosis and follow up the


response to therapy
1) Alpha fetoprotein antigen (AFP) in cases of hepatoma

2) Carcinoembryoinic antigen (CEA) in gastrointestinal tumors,


tumors of biliary system and cancer breast

3) Cancer antigen 125 (CA 125) in ovarian carcinoma

4) Cancer antigen 15-3 (CA15-3) in breast cancer

5) Cancer antigen 19-9 in colon and pancreatic tumor

6) Prostatic specific antigen (PSA) in prostatic tumors


a) Hormones :
- Human chorionic gonadotrophins (HCG) are secreted
in cases of choriocarcinoma
- Thyroxin (T3 & T4) is secreted in cases of cancer
of thyroid gland

b) Enzymes :
- Acid phosphatase enzymes in cases of cancer prostae

- Alkaline phosphatese, lipase and amylase enzymes in cases of


cancer pancreas
 Raise monoclonal antibodies
 Use antibodies for diagnosis
 Use antibodies for therapy

 Stimulate the in vivo specific response


 Specific active treatment
 Specific passive treatment
 Adjuvant therapy to augment specific
immunity

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active immunotherapy
specific killed tumor cells, purified or
recombinant Ag
non- BCG, Propionibacterium acne,
specific levamisole, etc.

passive immunotherapy
non-specific LAK cells, cytokines

specific antibodies alone or conjugated with


other agent, activated T cells

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 Modification by gene transfer
 Obj: selectively induced T-cell mediated
immune response  stimulate the local growth
of T cells or dendritic cells y the secretion of
cytokines (IL-2, IL-4, IL-7, Gm-CSF)
 Systemic administration of cytokines

 IFN-gamma : immunostimulatory effect, direct


antiproliferative effect