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

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

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

NORMAL CELLS
Oncogenesis. Mutations, Carcinogens, Irradiation, Viruses.

About 33% of the Regulated slow/no cell growth. known cancer risks Immune defenses: Contact growth inhibition. are avoidable. Cytotoxic Substrate dependent growth. T-cells, Smoking, obesity, Activated Active tumor suppressor genes.NK-cells, Activated sex and drugs. ALL ANTIGENS TOLERATED.Ms, NEOPLASTIC (Benign)
Immune antibodies. Increased growth. DNA synthesis. Errors permanent. Normal karyotype.

Accumulated errors: Innate defenses: Faster growth rate. Apoptosis, LossNatural killer cells, of regulation. Abnormal karyotype. Macrophages, Immortal, resistance to Natural antibodies, host Complement. defenses.

CELL DEATH METASTATIC

INVASIVE

(Malignant)

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 .

Cancer survival from diagnosis.

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

Most Cancers are Avoidable

Annual U.S. cancer deaths ~ 1 million. Avoidable cancer deaths for smokers:
Smoking. Sex, lifestyle. Sunlight UVB, bad air Work, alcohol. Diet, obesity, lethargy. 60% 2% (carcinomas) 0.4% (melanoma) 0.8% (thyroid, liver) 12% (cardiovascular)

Overall 750 thousand deaths are avoidable (Among non-smokers 50% are avoidable)
About 33% of cancers are treatable if detected early.

IS IMMUNOSURVEILLANCE IMPORTANT?
Patient Annual Adjusted Rate of group Incidence Risk growth Normal 1/300 1 None Allograft 1/100 25 Fast No T-cells 1/100 25 Very fast No B-cells 1/10 5,000 Fast S.C.I.D. 1/10 10,000 Very fast 1/10 5,000 Fast No NK/M

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.

TUMOR SPECIFIC ANTIGENS (TSA)

Mutated self proteins.

TUMOR SPECIFIC ANTIGENS (TSA) Re-expression of embryonic antigens. Overexpression of normal cell antigens. Oncogenic viral proteins.

(Epstein-Barr Virus)

Roitt

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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.

IF ALL CANCER CELLS ARE IMMUNOGENIC WHY IS CANCER SUCH A BIG PROBLEM? 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 cant be augmented? Therefore the cancer may not be rejected by the host!

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Tumor CD4+

Tumor

CD8+

Roitt et al

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Interaction between cancer and host resistance.

Cancer cells, herpes viruses.
Naive Th-cell Active Th-cell

T-reg cell

NK

Anergic T-cells.

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

NK-CELLS AND CYTOTOXIC T-CELLS KILL CANCER CELLS Tumor cells that have lost MHC may evade cytotoxic T-cells only to be attacked by NK-cells.

Janeway figure 14.15

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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 M mediated tumor cytotoxicity. Augment the Tc-cell mediated cytotoxicity. Develop anti-tumor antibodies, ADCC. Block the malignant/invasive phenotype. New technologies? Virolysis?

Roitt, Brostoff Male

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Roitt, Brostoff Male

Roitt, Brostoff Male

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TUMOR SPECIFC ANTIGENS AND IMMUNOTHERAPY.

BrCa1

Janeway figure 14.17

TUMOR SPECIFIC ANTIBODY IMMUNOTHERAPIES.

Janeway figure 14.16

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Large Tumor

Roitt, Brostoff and Male.

Roitt, Brostoff Male

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CONSTRUCTION OF IMMUNOGENIC TUMOR VACCINES

TRANSFECTION WITH B7 AUGMENTS TUMOR IMMUNTY.

Janeway figure 14.19

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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.

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