THE IMMUNOBIOLOGY OF CANCER

Diana Santos 172459Joana Paulo 172455

Instituto Superior TécnicoMestrado Integrado em Engenharia BiomédicaEngenharia Biomolecular e Celular

Outline

Bibliography

Hepatocelular Cancer

Immunosurveillance and Immunoediting

Innate and Adaptive Immunity

Cancer and its causes

Immunotherapy

Conclusion

Cancer Cellular proliferation in an uncontrolled way;

Reproduction and no differentiation;

Invasion of adjacent tissues and possible spread in the body – metastasis.

Benign ones

They are not capable of metastasis: they do not kill the host

cells

Tumors

Malign ones

They grow indefinitely and

spread, leading to metastasis

CANCER

Cancer Causes

External Factors leadingto cancer development

Carcinogenic Substances

UV and X Radiation

GeneticFactors

ViralInfections

Proto-Oncogenes:

They promote the cell growthThey turn the replication process possible

WHEN MUTATED -Oncogenes

Oncogenes: •Increase on transcription factors•Transcription factors receptor’s activation•Signal molecules mutation•Increase on the expression 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 replication

WHEN MUTATED

Cancer Causes

What’s Cancer

Cell Growth

BLA

BLA

BLA

BLA

Cancer’s Etiology

Growth Promoting

Growth Restricting

Proto-oncogenes

Tumor supressor

genes

Growth Promoting

Growth Restricting

Mutations

Cancer Causes

Innate and Adaptive Immunity

Innate and Adaptive Immunity

Immunosurveillance

• 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);

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

What’s Cancer

BLA

BLA

Tumor & Immunology

BLA

BLA

BLA

Anti-tumor Immunosurveillance evidence

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 treatments present a higher incidence of tumors;

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

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

Immunoediting

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

How can tumor cells avoid the Immunosurveillance?

• 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

Hepatocellular Carcinoma (HCC)

Hepatitis B Virus (HBV)

Implicate as the probable causes oh HCC in at least 80% of cases worldwide

Immune response against HCCCD4+

CD8+

16

Cell Type Mechanism

CD4+ T cells Deletion of helper CD4+ T cell

CD8+ T cells Exhaustion of CD8+ T cellsUpregulation of PD-1Reduced CD28 and CD3 ExpressionIncrease caspase-3 activity

DCs Reduced IL-12 production

Kupffer Cells Increased PD-L1 expression

MDSCs Induction of TregSuppression of NK cell numbers

Neutrophils Induction of angiogenesis

NK Cells Reduced NK cell numbersImpaired NK cell Cytotoxicity

TAM Induction of Treg and TC17/Th17 cells

TC17/Th17 cells Induction of angiogenesis by IL-17 production

Failure mechanisms of immune responses against HCC

How can we take advantage from immunobiologic response?

Immunotherapy

Administration of monoclonal antibodies which target either tumour-specific or over-expressed antigens.

Apoptosis induction

Complement-mediated

cytotoxicity

ADCC

NKMØ

Conjugated to toxin / isotope

Passive Immunotherapy

Vaccination strategies

Cell based Cytokines

• IL-2 • IFNs• TNFα

• Single peptide

• Multiple peptides

• HSP complexes

•Tumour-specific CTL

•Tumour-derived APC

•DC priming

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

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

• 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.

ConclusionsBibliography

Questions

“It 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)