1. Instituto Superior Técnico
Mestrado Integrado em Engenharia Biomédica
Engenharia Biomolecular e Celular
THE IMMUNOBIOLOGY OF CANCER
Diana Santos 172459
Joana Paulo 172455

2. Outline
Cancer and its causes
Innate and Adaptive Immunity
Immunosurveillance and Immunoediting
Hepatocelular Cancer
Immunotherapy
Conclusion
Bibliography

3. Cancer
 Cellular proliferation in an uncontrolled way;
 Reproduction and no differentiation;
 Invasion of adjacent tissues 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 Genetic Viral
Substances Radiation Factors Infections

5. Cancer Causes
Tumor suppressing
Oncogenes: genes:
•Increase on They can induce
transcription factors apoptosis or delay the
Proto-Oncogenes: •Transcription factors cell cycle, in order to
receptor’s activation have DNA reparation
They promote the cell •Signal molecules and to prevent
growth mutation uncontrolled cell
They turn the •Increase on the replication
replication process expression of anti- WHEN MUTATED
possible apoptotic genes
CANCER
WHEN MUTATED -
Oncogenes

6. What’s
Cancer Causes
Cancer
Cancer’s
Etiology
Cell Growth
Mutations
BLA
BLA
Growth
BLA Promoting
BLA
Growth
Restricting

7. Innate and Adaptive Immunity

8. Innate and Adaptive Immunity

9. Immunosurveillance
Lewis Thom as and Macfarlane Burnett
• IS is continuously able to supervise the organism and to
distinguish between tumor cells and others;
• Tumor cells are immunogenic and distinct from others
(antigenically);
Unless there is a mechanism that allows tumor cells to evade from IS
action, cancers would always be rejected

10. Anti-tumor
What’s
Cancer Immunosurveillance evidence
BLA
Micro tumors have a high incidence rate than cancers do;
BLA
Many cancers present in their composition immune cells;
Tumor &
Immunology
Tumors are more frequent in immunodeficient patients;
BLA
Transplanted patients, who made immunosupressor treatments
present a higher incidence of tumors;
BLA
Cancer is more likely to appear in advanced ages, when the immune
BLA system is lesser effective;
In some cases, in immunocompetent people, it is possible to occurs a
regression of the tumor;

11. Immunoediting

12. How can tumor cells avoid the
Immunosurveillance?
Immunologic tolerance (negative selection of T cells)
Immunosupressor cytokines (IL-10, TGF-β1, TGF-α)
Loss/Down-regulation 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

13. How can tumor cells avoid the
Immunosurveillance?

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

15.  Immune response against HCC
CD4+
CD8+

16.  Failure mechanisms of immune responses
against HCC
Cell Type Mechanism
CD4+ T cells Deletion of helper CD4+ T cell
CD8+ T cells Exhaustion of CD8+ T cells
Upregulation of PD-1
Reduced CD28 and CD3 Expression
Increase caspase-3 activity
DCs Reduced IL-12 production
Kupffer Cells Increased PD-L1 expression
MDSCs Induction of Treg
Suppression of NK cell numbers
Neutrophils Induction of angiogenesis
NK Cells Reduced NK cell numbers
Impaired NK cell Cytotoxicity
TAM Induction of Treg and TC17/Th17 cells
TC17/Th17 cells Induction of angiogenesis by IL-17 production 16

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

18.  Passive Immunotherapy
Administration of monoclonal antibodies which target
either tumour-specific or over-expressed antigens.
MØ NK
Apoptosis Complement- ADCC Conjugated to
induction mediated toxin / isotope
cytotoxicity

19.  Active Immunotherapy
• Single peptide
Vaccination
• Multiple peptides
strategies
• HSP complexes
Cell
Cytokines
based
•Tumour-specific CTL
• IL-2
•Tumour-derived APC
• IFNs
• TNFα
•DC priming

20.  Effective Therapies
Regression of a large liver
metastasis from kidney cancer in
a patient treated with IL-2.
Regression is ongoing seven
years later

21. Conclusions
Immune system plays a surveillance role in controlling the
development of cancer
Cancer development requires that malign cells escape from the
immune system action, trough a set of mechanisms

22. 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 therapeutic intervention." Seminars in Cancer
Biology 16(1): 3-15.
• Leon, K., K. Garcia, et al. (2007). "How Regulatory CD25+CD4+ T Cells
Impinge on Tumor Immunobiology: The Differential Response of Tumors to
Therapies." The Journal of Immunology 179(9): 5659-5668.
• 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.

23. Questions
W.H.Woglom, Cancer Research (1929)
“It would be as difficult to reject the right
ear and leave the left ear intact, as it is to
immunize against cancer”.