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MICROBIOLOGY AND IMMUNOLOGY

ADVANCED IMMNUOLOGY MIMM414

TUMOR IMMUNOLOGY AND IMMUNOTHERAPY.Lecture-37: Monday, November 27, 2006

http://www.mcgill.ca/microimm/undergraduate/courses/mimm414/

Professor Malcolm G. Baines

Malcolm.Baines@McGill.Ca

Sources of information for this lecture.• Janeway et al. Immunobiology. 6th Edition. Garland science,

2005. • Liotta, L.A. and E.C. Kohn. The microenvironment of the

tumour-host interface. [Review] [65 refs]. Nature 411: 375-379, 2001.

• Ponder, B.A. Cancer genetics. [Review] [73 refs]. Nature 411: 336-341, 2001.

• Smyth, M.J. and J.A. Trapani. Lymphocyte-mediated immunosurveillance of epithelial cancers? Trends in Immunology 22: 409-411, 2001.

• Mocellin S, Rossi C.R. and Nitti D. Cancer vaccine development: on the way to break immune tolerance to malignant cells. Experimental Cell Research 299: 267-278, 2004

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CURRENTLY, ABOUT 25% OF US WILL DIE OF CANCER!

THROUGHOUT HISTORY, INFECTIOUS DISEASE WAS THE PRIMIARY AGENT OF POPULATION CONTROL.

Regulated slow/no cell growth. Contact growth inhibition. Substrate dependent growth. Active tumor suppressor genes. ALL ANTIGENS TOLERATED.

Increased growth. DNA synthesis. Errors permanent. Normal karyotype.

CELL DEATH

Oncogenesis. Mutations, Carcinogens, Irradiation, Viruses.

Innate defenses:Apoptosis, Natural killer cells, Macrophages, Natural antibodies, Complement.

NORMAL CELLS

Accumulated errors:Faster growth rate. Loss of regulation. Abnormal karyotype. Immortal, resistance to host defenses.

Regulated slow/no cell growth. Contact growth inhibition. Substrate dependent growth. Active tumor suppressor genes. ALL ANTIGENS TOLERATED.

INVASIVE

METASTATIC

(Malignant)

NEOPLASTIC (Benign)

Immune defenses:Cytotoxic T-cells, Activated NK-cells, Activated MΦs, Immune antibodies.

About 33% of the known cancer risks

are avoidable. Smoking, obesity,

sex and drugs.

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A MULTI-STEP PROCESS LEADS TO CANCER.• A neoplastic cell is monoclonal, grows as a clone.• Some cancers will spontaneously regress or die.• Clonal growth rate is regulated by host resistance.• Clonal survival is controlled by immune responses.• Growth of cancer cells increases genetic instability. • Cancer develops as a process of clonal succession.• Most cancers will eventually grow progressively.• Ultimately the cancer wins the contest for nutrition .

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Cancer survival from diagnosis.• All cancers 58% @ 5 years.• Melanoma 80% @ 5 years.• Prostate 65% @ 5 years.• Colon 52% @ 5 years.• Breast 75% @ 5 years.• Cervix 69% @ 5 years.• Lung 11% @ 5 years.

Most Cancers are Avoidable• Annual U.S. cancer deaths ~ 1 million.• Avoidable cancer deaths for smokers:

– Smoking. 60% – Sex, lifestyle. 2% (carcinomas)– Sunlight UVB, bad air 0.4% (melanoma)– Work, alcohol. 0.8% (thyroid, liver)– Diet, obesity, lethargy. 12% (cardiovascular)

• Overall 750 thousand deaths are avoidable (Among non-smokers 50% are avoidable)

• About 33% of cancers are treatable if detected early.

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IS IMMUNOSURVEILLANCE IMPORTANT?

Patientgroup

AnnualIncidence

AdjustedRisk

Rate ofgrowth

Normal 1/300 1 NoneAllograft 1/100 25 FastNo T-cells 1/100 25 Very fastNo B-cells 1/10 5,000 FastS.C.I.D. 1/10 10,000 Very fastNo NK/MΦ 1/10 5,000 Fast

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MALIGNANT CELLS• No factor dependent growth regulation.• Loss of contact inhibition of growth.• Surface independent growth in suspension.• High mitotic index or 'S' phase fraction.• Produce angiogenic factors for nutrition.• Immortal (apoptosis inactivated/inhibited).• Loss of "tumor/growth suppressor genes”.• Abnormal DNA content (polyploidy).• Invasive phenotype, produce invasion factors.• Spread by metastasis, seed to other sites.

TUMOR CELLS ARE IMMUNOGENIC.

• Immunity is acquired through immunization with killed cells or during tumor growth.

• Immunity is specific for the antigens of the original tumor.

• Immunity is permanent.

• Immunity prevents the growth of limited numbers of tumor cells (metastasis) but does NOT cause the regression of the established primary tumor.

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Mutated self proteins.

TUMOR SPECIFIC ANTIGENS (TSA)

Over-expression of

normal cell antigens.

Re-expression of embryonic antigens.

TUMOR SPECIFIC ANTIGENS (TSA)

Oncogenic viral proteins.

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Roitt

(Epstein-Barr Virus)

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ANTIGENS OF CARCINOGEN versus VIRUS INDUCED CANCERS.

Virus induced tumors often contain virus specific antigens. The TSAs for carcinogen induced cancers are cancer specific but NOT related.

• The tumor TSA are often not strongly immunogenic?

• Tumor immunosuppression blocks the host response?

• The host response to TSAs usually not very quick?

• The host cytotoxic response to TSAs is not strong?

• The host response to TSAs can’t be augmented?

• Therefore the cancer may not be rejected by the host!

IF ALL CANCER CELLS ARE IMMUNOGENIC WHY IS CANCER SUCH A BIG PROBLEM?

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CD4+

CD8+Tumor

Tumor

Roitt et al

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Interaction between cancer and host resistance.

T-reg cell

Active Th-cell

Naive Th-cell

Anergic T-cells.

← Cancer cells, herpes viruses.

MΦ

NK

HOW CANCERS EVADE THE HOST RESPONSE

• Cancer cells grow and mutate faster and faster.• Expression of Fas-L induces death of immune cells.• Lack of co-stimulatory APCs can anergize T-cells.• Reduced expression of MHC antigens blocks CMI.• Altered glycosylation masks TSA recognition.• Immune complexes block many cytotoxic cells.• Immunosuppressive factors reduce host response.• Immunoregulatory cells impair the host response.• Cancer cells become immortal, anti-apoptosis.• Cancer cells can rapidly spread by blood or lymph.• When the cancer attains a critical mass, resistance

is suppressed and treatment is fundamentally futile.

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Janeway figure 14.13

Janeway figure 14.15

NK-CELLS AND CYTOTOXIC T-CELLS KILL CANCER CELLSTumor cells that have lost MHC may evade cytotoxic T-cells

only to be attacked by NK-cells.

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HOW CAN WE HELP THE HOST RESPONSE?• Detect cancers early when tumor is < 2 cm.• Develop cell growth regulatory agents.• Develop anti-angiogenic agents, starve Ca. • Augment NK surveillance against cancer.• Augment MΦ mediated tumor cytotoxicity.• Augment the Tc-cell mediated cytotoxicity.• Develop anti-tumor antibodies, ADCC.• Block the malignant/invasive phenotype. • New technologies? Virolysis?

Roitt, BrostoffMale

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Roitt, BrostoffMale

Roitt, BrostoffMale

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Janeway figure 14.17

TUMOR SPECIFC ANTIGENS AND IMMUNOTHERAPY.

BrCa1

Janeway figure 14.16

TUMOR SPECIFIC ANTIBODY IMMUNOTHERAPIES.

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Roitt, Brostoff and Male.

Large Tumor

Roitt, BrostoffMale

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CONSTRUCTION OF IMMUNOGENIC TUMOR VACCINES

Janeway figure 14.19

TRANSFECTION WITH B7 AUGMENTS TUMOR IMMUNTY.

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FUTURE FOR CANCER• More vaccines against oncogenic viruses.• Better cancer detection immunoassays.• More specific treatments with antibodies.• Cytokines to augment the CMI response.• Cancer specific drugs to regulate growth.• Gene therapy to increase tumor sensitivity.• Better monitoring of the effect of treatment.• More funding for cancer research.

HECTOR GERVAIS CANADIAN AND WORLD CHAMPION

Enjoy yourself now as you may not be able to later. Look after your health

now, avoid cancer.