immunobiology of cancer (final)

8/3/2019 Immunobiology of Cancer (FINAL)

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THE IMMUNOBIOLOGY OF CANCER

Diana Santos 72459Joana Paulo 72455

Instituto Superior Técnico

Mestrado Integrado em Engenharia Biomédica

Engenharia Biomolecular e Celular



Cancer CausesCancer Causes

External Factors leading

to cancer development

CarcinogenicSubstances UV and XRadiation

GeneticFactors

ViralInfections



Proto-Oncogenes:

They promote the cell

growth

They turn thereplication process

possible

WHEN MUTATED -

Oncogenes

Oncogenes:Increase on

transcription factors

Transcription factors

receptors activation

Signal molecules

mutation

Increase on theexpression of anti-

apoptotic genes

CANCER

Tumor suppressing

genes:They can induce

apoptosis or delay the

cell cycle, in order to

have DNA reparation

and to prevent

uncontrolled cell

replicationWHEN MUTATED




GrowthPromoting

GrowthRestricting

Mutations




Innate and Adaptive Immunity



Immune System is continuously able to supervise the organismand to distinguish between tumor cells and others;

Tumor cells are immunogenic and distinct from others(antigenically);

Immune System is continuously able to supervise the organismand to distinguish between tumor cells and others;

Tumor cells are immunogenic and distinct from others(antigenically);

Lewis Thom as and Macfarlane Burnett

Unless there is a mechanism that allows tumor cells to evade from IS

action, cancers would always be rejected

Immunosurveillance



Micro tumors have a high incidence rate than cancers do;

Many cancers present in their composition immune cells;

Tumors are more frequent in immunodeficient patients;

Transplanted patients, who made immunosupressor treatmentspresent a higher incidence of tumors;

Cancer is more likely to appear in advanced ages, when the immunesystem is lesser effective;

In some cases, in immunocompetent people, it is possible to occurs aregression of the tumor;

Anti-tumor Immunosurveillance evidence



Immunoediting

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



How can tumor cells avoid the

Immunosurveillance?

Immunologic tolerance (negative selection of T cells)

Immunosupressor cytokines (IL-10, TGF-1, TGF-)

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, bytumor cells



How can tumor cells avoid the

Immunosurveillance?

Theresa L, W. (2006)



Primary liver cancer is the fifth most common cancer in the worldand the third most common cause of cancer mortality

Hepatocellular carcinomas (HCCs) are malignant tumors of liver

parenchymal cells

Hepatocellular Carcinoma (HCC)

Hepatitis B Virus (HBV)

probable causes of HCC inprobable causes of HCC in

at least 80% of casesat least 80% of cases

worldwideworldwide



Immune response against HCC

CD4+

CD8+

Flecken, T., H. Spangenberg, et al. (2011)



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 ExpressionIncrease 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 15

Failure mechanisms of immune

responses against HCC



How can we take advantage fromimmunobiologic response?

Immunotherapy



Administration of monoclonal antibodies which target

either tumour-specific or over-expressed antigens.

Apoptosisinduction

Complementedcytotoxicity

ADCC

NKMØ

Conjugated totoxin / isotope

Passive Immunotherapy



Vaccinationstrategies

Cellbased

Cytokines

IL-2 IFNs TNF

HSP complexes

Single peptide

Multiple peptides

HSP complexes

Dendritc Cells

Tumour-specific CTL

Tumour-derived APC

Dendritc Cells

Active Immunotherapy



Effective Therapies

Regression of a large liver

metastasis from kidney cancer in

a patient treated with IL-2.

Regression is ongoing seven

years later

Rosenberg (2001)



³It would be as difficult to reject the right

ear and leave the left ear intact, as it is to

immunize against cancer.

W.H.Woglom,Cancer Research

(1929)

Conclusions

Immune system plays a surveillance role in controlling thedevelopment of cancer

Cancer development requires that malign cells escape fromthe immune system action, trough a set of mechanisms

Tumors like HCC are globally increasing

Further research is needed to better understand failure mechanismsof immune systems and eventually be able to overcome it.



ConclusionsBibliography 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.

Dunn, G. P., L. J. Old, et al. (2004). "The Immunobiology of CancerImmunosurveillance and Immunoediting." 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):25572576.

Spangenberg HC, Thimme R, Blum HE (2009) Targeted therapy for

hepatocellular carcinoma. Gastroenterology 6 (7):423432.

Flecken, T., H. Spangenberg, et al. (2011) "Immunobiology of hepatocellular

carcinoma." Langenbeck's Archives of Surgery: 1-8.

Coplandet al

(2005) Cancer Immunol. Immunother. 54:297



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immunobiology of cancer (final)

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