Cancer and the immune system

BS963 Elena Klenova, e-mail: klenovae@essex.ac.uk

Recommended reading
• Immunobiology : the immune system in health and disease /Charles A. Janeway, Paul Travers, Mark Walport and Mark Shlomchik; 2005, Garland Science Publishing • Janeway's immunobiology 7th ed. / Kenneth Murphy, Paul Travers, Mark Walport ; with contributions by Michael Ehrenstein ... [et al.]; 2009, Garland Science Publishing • The Immune system/Peter Parham, 2005, Garland Science Publishing • Cellular and molecular immunology / Abul K. Abbas, Andrew H. Lichtman, Shiv Pillai/ 2007, Philadelphia : Saunders Elsevier ( also the 2005 Edition) • Dunn GP, Koebel CM, Schreiber RD: Interferons, immunity and cancer immunoediting. Nature Reviews Immunology 2006, 6:836-848. • Ichim, C.V. Revisiting immunosurveillance and immunostimulation: Implications for cancer immunotherapy J Transl Med 3, 8 (2005). • Pardoll D. Does the immune system see tumors as foreign or self? Annu. Rev. Immunol. 2003, 21:807-39 • Smyth, M. J. et al. A fresh look at tumor immunosurveillance and immunotherapy. Nature Immunology 2001, 2: 293 – 299.

Plan of the seminar
1. General Introduction ( Cancer and Immune system). 2. Theories of the role of the immune system in cancer. 3. Cells of the immune system involved in anti-tumour response and basic mechanisms of anti-tumour immunity. 4. Tumours antigens: novel or over-expressed proteins produced by tumours that may be recognized by the immune system. 5. How do tumour cells escape from the immune system? 6. Anti-tumour therapy. Anti-tumour vaccines.

1. General Introduction ( Cancer and Immune system).

a tumour that is not capable of indefinite growth. • Benign .a tumour that grows indefinitely and often spreads (metastasis). It does not kill the host. . • Malignant . It can kill the host.Cancer • Uncontrolled growth produces a tumour ( neoplasm).

Skin or epithelial lining of organs.Types of Cancer (based on the type of affected tissue) • Carcinoma: Cancer of endo or ectoderm e. bone. • Sarcomas: Cancer of mesoderm e.g.g. • Leukemias and Lymphomas: Cancers of hematopoietic cells .

Macrophages) – immediately available for combat • Adaptive (specific) immune system (T – and B-Lymphocytes) – Production of antibody (Ab) or cells specific to combat a particular antigen .The Immune System • Innate (non-specific) immune system (Granulocytes.

and Adaptive immune responses utilize the machinery of innate immunity for effector function .Innate and adaptive responses work together Innate  Antigen independent  Immediate (hours)  Neutrophils  NK (Natural Killer) cells  Macrophages Adaptive Antigen-dependent Slower (days) T cells B cells Dendritic cells – a link between the innate and adaptive systems! Innate immune responses help form adaptive immune responses.

Evidence for the role of immune system in tumor rejection • Spontaneous regression • Regression of metastases after removal of primary tumor • Regression after chemotherapy • Infiltration of tumors by lymphocytes and macrophages • Lymphocyte proliferation in draining lymph nodes • Higher incidence of cancer after immunosuppression/immunodeficiency (AIDS. neonates. aged. transplant patients) .

Tumour rejection antigens are specific for individual tumours .

2. Theories of the role of the immune system in cancer. .

the tumoursuppressing role of the immune system. • Tumour and immune system interact: mutual influence! . • Immunostimulation .the tumourpromoting role of the immune system.Two distinct theories of the role of the immune system in cancer • Immunosurveillance .

• In the late 1950s Lewis Thomas introduced the theory of immunosurveillance. •The theory states that immunosurveillance is a physiologic function of the immune system. Cancerous cells seen as foreign and thus can be constantly eliminated by immune surveillance. C. . J Transl Med 3. Ichim. which was subsequently developed by Sir MacFarlane Burnet .V. 8 (2005).Immunosurveillance (immune surveillance ) • As early as 1909 Paul Ehrlich postulated that cancer occurs spontaneously in vivo and that the immune system is able to both recognize and protect against it .

Cancer immunosurveilance: evidence in humans • Increased incidence of virally-induced tumours in Immunosuppressed patients • Studies showing increase in de novo malignant melanoma in organs transplant patients • 25-fold increase in incidence of lung carcinoma in cardiac transplant patients • Reverse correlations between tumour infiltrating lymphocytes and tumour survival Dunn et al. Nature Reviews Immunology 6. 836–848 (2006) .

836–848 (2006) . Nature Reviews Immunology 6.Cancer immunosurveilance: evidence in mice Dunn et al.

•In 1972. Richmond Prehn formulated the theory of immunostimulation of tumour growth. such as that generated by spontaneous tumors. This theory states that. in contrast to the strong immune response generated by transplantable tumours. . who showed that injection of dead autologous tumour cells enhanced the growth of pre-existing tumours.Immunostimulation (immune stimulation) • The proof of the principle that an inappropriate type of immune response will enhance tumour growth was demonstrated as early as 1907 by Flexner and Jobling. is stimulatory to the growth of neoplasia. a quantitatively mild immune response.

3.How the conflicting roles of the immune response in neoplasia can be explained? Modern view: The immune system is not a single entity.tumour cells evolved enough to grow unimpeded and form a tumour . Tumour cells undergo changes in a process called immunoediting. but a complex system of constituents.recognition and destruction of the tumour cells 2. “Escape phase”. The concept of immunosurveillance has been modified and is now considered in three phases: 1. “Elimination phase” . “Equilibrium phase” – occurs if elimination is not successful.

. Cells of the immune system involved in anti-tumour response and basic mechanisms of antitumour immunity.3.

These new or altered antigens flag immune defenders. and macrophages. including cytotoxic T cells. IFN-g Natural IFN-g When normal cells turn into cancer cells. some of the antigens on their surface change.The immune system provides one of the body's main defenses against cancer. natural killer cells. .

Immune cells are generated during hematopoiesis .

Cells of the immune system involved in tumour response Functions: Phagocytosis Antigen presentation to T cells Phagocytosis of microorganisms and antigen presentation to T cells Kill tumor and virus-infected cells Regulates humoral and cell-mediated immune responses .

in the peripheral lymphoid system. CD8 occurs during their development in the thymus. T-cells clonally expand as a result of IL-2 secretion forming a population of T-cells with the same antigen specificity----further differentiation into memory & effector cells . . also known as Th1 and Th2. further subdivided into type 1 and type 2. The differentiation of Th cells into Th1 and Th2 occurs only after these cells have been activated during an immune response.Only recognize antigen bound to MHC class II molecule • CD 8 + cytotoxic T cells (TC) -Only recognize antigen bound to MHC class I molecules • T cells require two signals for activation: 1 -from TCR /MHC-antigen complex & CD4 or CD8/MHC complex 2-from an accessory molecule CD28 When all appropriate signals are received. T cells: CD 4 & 8 Accessory Molecules • CD4 + helper T cells (TH). •The differentiation of T cells into CD4 vs.T-cell classification •Classification is based on the Structure & antigen specificity of TCR (T-cell receptor) •T cells are divided into two major groups: CD4+ T-helper and CD8+ T-cytotoxic cells.

CD 4 + (Th cells) -recognize antigen on MHC II .MHC genes highly polymorphic-within each species there are many different forms (alleles) • MHC function as antigen-recognition molecules .Can bind to a spectrum of antigenic peptides.Present exogenous antigen . polymorphism allows for diversity in antigen recognition • MHC I ---expressed on all nucleated cells .Present endogenous antigens -CD 8 + (Tc cells) -recognize antigen on MHC I • MHC II ---expressed on Antigen presenting cells (APC) .Class I and Class II MHC molecules .MHC-Major Histocompatibility Complex: Role of MHC Molecules • Membrane-bound glycoproteins .

Anti-tumour immunity: basic mechanisms Immunology 7th Ed ( D. Male et al) .

Blymphocytes. neutrophils. but not good stimulators of adaptive T cell responses • Once they are activated. they secrete cytokines to initiate inflammation and then they migrate to lymph nodes and mature • As mature DCs they are very efficient APCs for T cell stimulation • Other APCs: macrophages. they are highly phagocytic. . monocytes.Antigen – presenting cells (APC) Dendritic Cells (DC) • DCs are the interface between innate and adaptive immunity • DCs are immature as they circulate waiting to encounter pathogens. At this point.

M. cytokines.Anti-tumour immunity: basic mechanisms •Presence of tumour cells and tumour antigens may initiate the release of “danger” signals. • Activation and maturation of dendritic cells. migration from the lymph node • Subsequent T cell mediated destruction of tumour cells Smyth. uric acid etc. which present tumour antigens to CD8 and CD4 cells • Clonal expansion of CD8 and CD4 T cells.299 (2001) . 293 . et al. J. Nature Immunology 2. heat shock proteins (HSP).

The cellular basis of tumour immunology: CTL .tumor cell interactions .

Antigen presentation by antigen presenting cells .

Activated by IFN-a/b or IL-12 (produced rapidly by activated macrophages) Fig 8-3 .Activated NK cells secrete IFNg.Can mediate Antibody-Dependent Cellular Cytotoxicity (ADCC). (mechanism of immunologic lysis in which cellular targets sensitized by specific antibodies are efficiently and selectively lysed by nonspecific effectors) .Natural Killer (NK) Cells .Kill virally-infected cells with missing MHC class I .Kill target cell by release of cytotoxic granules containing granzymes and perforin which penetrate target cell membrane and induce programmed cell death .First identified by having the ability to lytically kill certain tumor cell lines without prior sensitization . acts on macrophages to increase microbial phagocytosis and killing .

Basic facts about NK cells They get easily activated. . do not adapt and kill MHC-negative cells.

.4. Tumours antigens: novel or over-expressed proteins produced by tumours that may be recognized by the immune system.

TATA: shared by normal and tumour cells Tumour-associated developmental Ag (TADA) Tumour-associated viral Ag (TAVA) Tumour-associated transplantation Ag .Antigens expressed on tumour cells Major Histocompatability Complex antigens TSTA Tumour-specific transplantation Ag TATA TSTA: unique to a tumour Play an important role in tumor rejection.

• Do not trigger anti-tumor immunity. –Alpha-fetoprotein(AFP) Cancers of liver –Carcinoembryonic Ag (CEA) colorectal cancer .Tumor-Associated Developmental Antigens • Found on cancer cells and on fetal cells. • Used in diagnosis.

Identification of tumour antigens • Use the immune system as a tool for the identification of immunogenic antigens • Gene profiling – genomics or transciptomics • Proteomic approaches – peptidomics. serum profiling • In-silico bioinformatic approaches – probing EST databases .

WT1 • Some additional antigens MUC-1 (over-expressed) Unique tumour antigens Point mutations: p53.Other Tumor associated antigens Shared tumour antigens: common in different tumours • Cancer-testis antigens MAGE family etc. Bcr/Abl • – viral antigens: HPV. gp100 • Over-expressed proto-oncogenes HER2/neu. • Differentiation antigens Melan-A/MART-1. Raf. EBV etc. .

5. How do tumour cells escape from the immune system? .

Malignant cells can be controlled by immunosurveillance NK – Natural Killers CD4. CD8 and gd – types of T-lymphocytes .

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6. Anti-tumour vaccines. Anti-tumour therapy. .

displays tumour-specific expression . .plays an important functional role in cell survival / differentiation / metastasis etc.is immunogenic .Ideal tumour antigen: .

g.Anti-tumour therapy  Specific Active Immunization: Vaccination with viral Antigens: e.  Ab Therapy Abs specific for oncogene product e. Abs against HER2/neu (Herceptin or trastuzumab) .g.  Hepatitis B virus Human Papilloma virus (HPV) – success story.

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bladder carcinoma Irradiated tumour cells ( with or without BCG) Normal Macro phage Tumor Activated Macro phage Tumor lysis .melanoma.Nonspecific: BCG (Bacillus Calmette-Guerin) Mycobacteria used as an adjuvant .

Antibody-Dependent Cellular Cytotoxicity (ADCC) Gene therapy Introduce cytokine genes for IL-2. Adoptive immunotherapy – ex vivo manipulation and transfer of effector cells . IFN-g etc into tumor cells to induce immune response. IL-4. IL-12. IL-2 tumour T cell IFN-g Macrophages .