1. InsCtuto
Superior
Técnico
Mestrado
Integrado
em
Engenharia
Biomédica
Engenharia
Biomolecular
e
Celular
THE
IMMUNOBIOLOGY
OF
CANCER
Diana
Santos
72459
Joana
Paulo
72455

2. Outline
Cancer
and
its
causes
Innate
and
Adap9ve
Immunity
Immunosurveillance
and
Immunoedi9ng
Hepatocelular
Cancer
Immunotherapy
Conclusion
Bibliography

3. Cancer
v Cellular
proliferaCon
in
an
uncontrolled
way;
v ReproducCon
and
no
differenCaCon;
v Invasion
of
adjacent
Cssues
and
possible
spread
in
the
body
–
metastasis.
Tumors
Benign
ones
Malign
ones
They
are
not
capable
They
grow
of
metastasis:
they
indefinitely
and
do
not
kill
the
host
spread,
leading
to
cells
metastasis
CANCER

4. Cancer
Causes
External Factors leading
to cancer development
Carcinogenic
UV
and
X
Gene9c
Viral
Substances
Radia9on
Factors
Infec9ons

5. Cancer
Causes
Tumor
suppressing
Oncogenes:
genes:
• Increase
on
They
can
induce
transcripCon
factors
apoptosis
or
delay
the
Proto-­‐Oncogenes:
• TranscripCon
factors
cell
cycle,
in
order
to
receptor’s
acCvaCon
have
DNA
reparaCon
They
promote
the
cell
• Signal
molecules
and
to
prevent
growth
mutaCon
uncontrolled
cell
They
turn
the
• Increase
on
the
replicaCon
replicaCon
process
expression
of
anC-­‐ WHEN
MUTATED
possible
apoptoCc
genes
CANCER
WHEN
MUTATED
-­‐
Oncogenes

6. Cancer
Causes
Muta9ons
Growth
Promo9ng
Growth
Restric9ng

7. Innate
and
AdapCve
Immunity

8. Immunosurveillance
Lewis
Thom
as
and
Macfarlane
BurneM
• Immune
System
is
conCnuously
able
to
supervise
the
organism
and
to
disCnguish
between
tumor
cells
and
others;
• Tumor
cells
are
immunogenic
and
disCnct
from
others
(anCgenically);
Unless
there
is
a
mechanism
that
allows
tumor
cells
to
evade
from
immune
system
ac9on,
cancers
would
always
be
rejected

9. Ø An9-­‐tumor
Immunosurveillance
evidence
Micro
tumors
have
a
high
incidence
rate
than
cancers
do;
Many
cancers
present
in
their
composiCon
immune
cells;
Tumors
are
more
frequent
in
immunodeficient
paCents;
Transplanted
paCents,
who
made
immunosupressor
treatments
present
a
higher
incidence
of
tumors;
Cancer
is
more
likely
to
appear
in
advanced
ages,
when
the
immune
system
is
lesser
effecCve;
In
some
cases,
in
immunocompetent
people,
it
is
possible
to
occurs
a
regression
of
the
tumor;

10. ImmunoediCng
Dunn,
G.
P.,
L.
J.
Old,
et
al.
(2004).

11. Ø How
can
tumor
cells
avoid
the
Immunosurveillance?
Immunologic
tolerance
(negaCve
selecCon
of
T
cells)
Immunosupressor
cytokines
(IL-­‐10,
TGF-­‐β1,
TGF-­‐α)
Loss/Down-­‐regulaCon
of
MHC-­‐I
molecules
Immunosuppressive
cells
(T
regulatory
cells,
NKT
cells)
T
and
NK
cells
apoptosis
due
to
FasL
high
expression
levels,
by
tumor
cells

12. Ø How
can
tumor
cells
avoid
the
Immunosurveillance?
Theresa
L,
W.
(2006)

13. Hepatocellular
Carcinoma
(HCC)
• Hepatocellular
carcinomas
(HCCs)
are
malignant
tumors
of
liver
parenchymal
cells
• Primary
liver
cancer
is
the
fihh
most
common
cancer
in
the
world
and
the
third
most
common
cause
of
cancer
mortality
Hepatitis B Virus (HBV)
probable
causes
of
HCC
in
at
least
80%
of
cases
worldwide

14. Ø Immune
response
against
HCC
CD4+
CD8+
• Flecken,
T.,
H.
Spangenberg,
et
al.
(2011)

15. Ø Failure
mechanisms
of
immune
responses
against
HCC
Cell
Type
Mechanism
CD4+
T
cells
DeleCon
of
helper
CD4+
T
cell
CD8+
T
cells
ExhausCon
of
CD8+
T
cells
UpregulaCon
of
PD-­‐1
Reduced
CD28
and
CD3
Expression
Increase
caspase-­‐3
acCvity
DCs
Reduced
IL-­‐12
producCon
Kupffer
Cells
Increased
PD-­‐L1
expression
MDSCs
InducCon
of
Treg
Suppression
of
NK
cell
numbers
Neutrophils
InducCon
of
angiogenesis
NK
Cells
Reduced
NK
cell
numbers
Impaired
NK
cell
Cytotoxicity
TAM
InducCon
of
Treg
and
TC17/Th17
cells
TC17/Th17
cells
InducCon
of
angiogenesis
by
IL-­‐17
producCon
15

16. How
can
we
take
advantage
from
immunobiologic
response?
Immunotherapy

17. Ø Passive
Immunotherapy
AdministraCon
of
monoclonal
anCbodies
which
target
either
tumour-­‐specific
or
over-­‐expressed
anCgens.
MØ NK
Apoptosis Complemented ADCC Conjugated to
induction cytotoxicity toxin / isotope

18. Ø Ac9ve
Immunotherapy
• Single peptide
Vaccination • Multiple peptides
strategies
• HSP Complex
Cell
Cytokines
based
• Tumour-specific CTL
• IL-2
• Tumour-derived APC
• IFNs
• TNFα
• Dendritc Cells

19. Ø Effec9ve
Therapies
Regression
of
a
large
liver
metastasis
from
kidney
cancer
in
a
pa9ent
treated
with
IL-­‐2.
Regression
is
ongoing
seven
years
later
Rosenberg (2001)

20. Conclusions
Immune
system
plays
a
surveillance
role
in
controlling
the
development
of
cancer
Cancer
development
requires
that
malign
cells
escape
from
the
immune
system
acCon,
through
a
set
of
mechanisms
Tumors
like
HCC
are
globally
increasing
Further
research
is
needed
to
beoer
understand
failure
mechanisms
of
immune
systems
and
eventually
be
able
to
overcome
it.
It
would
be
as
difficult
to
reject
the
right
ear
and
leave
the
leh
ear
intact,
as
it
is
to
immunize
against
cancer”.
W.H.Woglom,
Cancer
Research
(1929)

21. Bibliography
Conclusions
• Visser,
K.
E.,
A.
Eichten,
et
al.
(2006).
"Paradoxical
roles
of
the
immune
system
during
cancer
development."
Nat
Rev
Cancer
6(1):
24-­‐37.
• Theresa
L,
W.
(2006).
"Immune
suppression
in
cancer:
Effects
on
immune
cells,
mechanisms
and
future
therapeuCc
intervenCon."
Seminars
in
Cancer
Biology
16(1):
3-­‐15.
• Dunn,
G.
P.,
L.
J.
Old,
et
al.
(2004).
"The
Immunobiology
of
Cancer
Immunosurveillance
and
ImmunoediCng."
Immunity
21(2):
137-­‐148.
• Rosenberg
(2001)
Nature,
411;381-­‐4
• El-­‐Serag
HB,
Rudolph
KL
(2007)
“Hepatocellular
carcinoma:
epidemiology
and
molecular
carcinogenesis”.
Gastroenterology
132(7):2557–2576.
• Spangenberg
HC,
Thimme
R,
Blum
HE
(2009)
“Targeted
therapy
for
hepatocellular
carcinoma”.
Gastroenterology
6
(7):423–432.
• Flecken,
T.,
H.
Spangenberg,
et
al.
(2011)
"Immunobiology
of
hepatocellular
carcinoma."
Langenbeck's
Archives
of
Surgery:
1-­‐8.
• Copland
et
al
(2005)
Cancer
Immunol.
Immunother.
54:297

22. Thanks
for
your
aoenCon!
Questions