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).

Cancer
Uncontrolled growth produces a tumour ( neoplasm).

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

Types of Cancer (based on the type of affected tissue)

Carcinoma: Cancer of endo or ectoderm e.g. Skin or epithelial lining of organs. Sarcomas: Cancer of mesoderm e.g. bone.
Leukemias and Lymphomas: Cancers of hematopoietic cells

The Immune System

Innate (non-specific) immune system (Granulocytes, 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

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, and Adaptive immune responses utilize the machinery of innate immunity for effector function

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.

Two distinct theories of the role of the immune system in cancer

Immunosurveillance - the tumoursuppressing role of the immune system. Immunostimulation - the tumourpromoting role of the immune system.

Tumour and immune system interact: mutual influence!

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 . In the late 1950s Lewis Thomas introduced the theory of immunosurveillance, which was subsequently developed by Sir MacFarlane Burnet . 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.
Ichim, C.V. J Transl Med 3, 8 (2005).

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, 836848 (2006)

Cancer immunosurveilance: evidence in mice

Dunn et al. Nature Reviews Immunology 6, 836848 (2006)

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, who showed that injection of dead autologous tumour cells enhanced the growth of pre-existing tumours.

In 1972, Richmond Prehn formulated the theory of immunostimulation of tumour growth. This theory states that, in contrast to the strong immune response generated by transplantable tumours, a quantitatively mild immune response, such as that generated by spontaneous tumors, is stimulatory to the growth of neoplasia.

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

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

The immune system provides one of the body's main defenses against cancer.

IFN-g Natural

IFN-g

When normal cells turn into cancer cells, some of the antigens on their surface change. These new or altered antigens flag immune defenders, including cytotoxic T cells, natural killer cells, and macrophages.

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

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. The differentiation of T cells into CD4 vs. CD8 occurs during their development in the thymus.

T cells: CD 4 & 8 Accessory Molecules

CD4 + helper T cells (TH); further subdivided into type 1 and type 2, also known as Th1 and Th2. The differentiation of Th cells into Th1 and Th2 occurs only after these cells have been activated during an immune response, in the peripheral lymphoid system. - 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 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

MHC-Major Histocompatibility Complex: Role of MHC Molecules

Membrane-bound glycoproteins - Class I and Class II MHC molecules - 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; 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) - Present exogenous antigen - CD 4 + (Th cells) -recognize antigen on MHC II

Anti-tumour immunity: basic mechanisms

Immunology 7th Ed ( D. Male et al)

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, they are highly phagocytic, 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, neutrophils, Blymphocytes, monocytes.

Anti-tumour immunity: basic mechanisms

Presence of tumour cells and tumour antigens may initiate the release of danger signals; cytokines, heat shock proteins (HSP), uric acid etc. Activation and maturation of dendritic cells, which present tumour antigens to CD8 and CD4 cells Clonal expansion of CD8 and CD4 T cells; migration from the lymph node Subsequent T cell mediated destruction of tumour cells

Smyth, M. J. et al. Nature Immunology 2, 293 - 299 (2001)

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

Antigen presentation by antigen presenting cells

Natural Killer (NK) Cells

- First identified by having the ability to lytically kill certain tumor cell lines without prior sensitization - Kill target cell by release of cytotoxic granules containing granzymes and perforin which penetrate target cell membrane and induce programmed cell death - 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)

- Kill virally-infected cells with missing MHC class I - Activated by IFN-a/b or IL-12 (produced rapidly by activated macrophages)
Fig 8-3

- Activated NK cells secrete IFNg, 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.

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. TATA: shared by normal and tumour cells Tumour-associated developmental Ag (TADA) Tumour-associated viral Ag (TAVA)

Tumour-associated transplantation Ag

Tumor-Associated Developmental Antigens

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

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

Other Tumor associated antigens

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

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

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

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

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

Tumor

Activated Macro phage

Tumor lysis

 Adoptive immunotherapy ex vivo manipulation and transfer of effector cells

- Antibody-Dependent Cellular Cytotoxicity (ADCC)

Gene therapy
Introduce cytokine genes for IL-2, IL-4, IL-12, IFN-g etc into tumor cells to induce immune response. IL-2 tumour T cell

IFN-g
Macrophages