Download 11. Cancer and the Immune System

11.
Cancer and the Immune System
(มะเร็งก ับระบบภูมค
ิ ม
ุ ้ ก ัน )
Objectives


Students should be able to explain cell-mediated
immune response and immunological tolerance.
Students should be able to describe how to induce
tumor immunity.
Contents
11.1 Introduction
11.2 Biology of the immune system
11.3 Tolerance and the immune system
11.4 Tumor Immunology
11.5 Induction of Tumor Immunity
11. Cancer and the immune system
11.1 Introduction
 Antigens are substances, usually foreign, that are specifically
recognized by receptors on the cells of the immune system.
 Adaptive immunity is the antigen-specific host defense that is
mounted following exposure to antigen involving lymphocytes and
their products.
 Innate immunity results from a collection of cells and factors that
constitute the early host defense system.
 Immune system has ability to respond to foreign antigen but not to
self-antigen.
----> Self / Nonself – discrimination or self-tolerance
 An immune response against self-antigen would result in tissue
damage or autoimmunity.
11.2 Biology of the immune system
11.2.1 Adaptive Immunity
 responsible for the induction of immunity and immunological
memory upon exposure to foreign antigens.
 T and B lymphocytes are an integral part of the adaptive immune
system.
 B and T lymphocytes activation is triggered by different forms of
the antigen.
 The antigen receptors on lymphocytes recognize small parts of
proteins or peptides called “epitopes”.
 B cells are triggered by membrane-bound immunoglobulin
molecules (B-cell receptor; BCR) interacting with intact protein
antigen.
 T cells recognize peptide antigens bound to MHC molecules on the
surface of antigen presenting cells (APCs) or target cells.
1) T helper (Th) cells, together with CD4, recognize peptide presented
by MHC class II molecules on APCs.
2) Cytotoxic T Lymphocytes (CTLs), together with CD8, recognize
peptide presented by MHC class I molecules on APCs or target cells.
BCR
TCR
CD4
MHC II
TCR
CD8
MHC I
 Recognition of antigen initiates an immune response.
 Activated B lymphocytes proliferate and differentiate into plasma cells that
secrete soluble immunoglobulin (antibody) molecules responsible for
humoral (antibody-mediated) immunity.
 Activated T lymphocytes are responsible for cell-mediated immunity.
 Strategies for immunotherapy of cancer are directed most often to the
activation of CTLs.
11.2.2 The Major Histocompatibility Complex (MHC)
 3 classes
1) Class I MHC
: expressed on virtually all cells
: transmembrane glycoproteins
2) Class II MHC
: expressed only on APCs
: transmembrane glycoproteins
3) Class III MHC
: components of the complement
system
: some cytokines (TNF-, TNF-)
Antigen processing and
presentation by MHC class
I and class II molecules.
Chaperone
 In the mouse, MHC = H-2 complex
: MHC class I ; H-2D, H-2K, H-2L
: MHC class II; I-A, I-E
 In human, MHC = HLA (human leukocyte antigen) complex
: MHC class I ; HLA-A, HLA-B, HLA-C
: MHC class II ; HLA-DQ, HLA-DR, HLA-DP
 MHC class I generally binds endogenous peptides, whereas MHC class II
generally binds exogenous peptides.
 However, cross-presentation can occur wherein extracellular soluble
antigen can be presented by MHC class I molecules.
11.2.3 T lymphocytes
1) Cytotoxic T lymphocytes (CTLs)
- function primarily to eliminate virally infected cells.
- potentially play a role in the elimination of tumor cells.
- express the coreceptor CD8.
- recognize peptide antigen presented by MHC class I.
- secrete a pore-forming protein, “perforin” , to facilitate the delivery of
enzymes (granzyme B) to target cells to activate cell death.
- CTL response is desired for anti-tumor immunity.
2) T helper cells (Th cells)
- function primarily to regulate other cells of the immune system by
secreting a range of cytokines.
- Cytokines act as growth factors for the proliferation and differentiation of
antigen-triggered CD8+ T cells, CD4+ T cells, and B cells.
- 3 types of Th cells
1) Th 1 cells:-secrete interleukin (IL)-2, interferon- (INF  ), and
granulocyte macrophage colony-stimulating factor (GM-CSF)
---> involved in cell mediated branch of the immune response
2) Th 2 cells:-secrete IL-4, IL-5, IL-10, IL-13, and GM-CSF
---> involved in activation of B cells and the humoral (antibodymediated) arm of the immune response.
3) Th 3 cells:-secrete transforming growth factor (TGF)- or IL-10
---> believed to assist in regulating immune response
11.2.4 T-cell receptor and T-cell recognition
 Interactions between T cells and APCs or target cells involve the ligation
of adhesion molecules on opposing cells.
 T cells with TCR :- 90-95% found in blood, thymus, lymph nodes, and
spleen
-----> primarily responsible for the antigen-specific immune response.
 T cells with TCR :- present in high numbers in the skin and intestinal
epithelium.
11.2.5 Overview of the Immune Response
 requires the presentation of antigen by mature professional APCs
(macrophages, dendritic cells (DCs), and activated B cells)
 Activated lymphocytes differentiate into effector or memory cells.
1. Effector cells
: Activated B cells produce antibodies
: CTLs eliminate target cells (virally infected cells or tumor cells)
2. Memory cells
: Some lymphocytes develop into memory cells and survive for long
periods of time on the periphery (unknown mechanism).
: Rapid immune response is mounted upon subsequent exposure to the
same antigen.
11.2.6 Overview of Lymphocyte activation
 Antigens can be found essentially anywhere in the body, but T
lymphocytes found primarily in the secondary lymphoid tissues (spleen and
lymph nodes) and in the circulation.
 Dendritic cells (DCs) express MHC class I and II molecules important for
activating T lymphocytes and for adhesion and costimulation of the immune
response.
Lymphocyte activation
CD40L
CD40
 Stimuli, such as
infectious agents,
induce maturation
and mobilization of
dendritic cells.
 DCs attract T cells
and B cells to the Tcell areas of the
lymphoid organs,
creating a
microenvironment
where lymphocyte
activation and an
immune response can
be generated.
 Cross presentation : DCs endocytose infected cells, then present
exogenous antigen to CTLs after DC maturation.
 CD40 ligation is required for the maturation of DCs.
11.3 Tolerance and the immune system
11.3.1 T-cell development
 T cells develop and mature in the thymus from immature T cells called
“thymocytes”.
 The fate of the developing thymocyte is determined by TCR interactions.
Basic stages of thymocyte development
Th
CTL
 Positive selection :
- Thymocytes that express a TCR capable of interacting weakly with
self MHC molecules are chosen to differentiate and survive.
- Thymocytes that are positively selected by recognizing MHC class
II/peptide complex will downregulate CD8 to become CD4+ thymocytes.
 Negative selection :
- The elimination of thymocytes that express a TCR with high affinity for self
MHC/self peptides complexes.
Thymic stromal cells
thymocytes
Stromal cells include thymic
cortical epithelial cells, thymic
medullary epithelial cells, and
dendritic cells.
http://www.nature.com/nri/journal/v2/n5/fig_tab/nri798_F1.html
11.3.2 Central Tolerance
- Central tolerance is the mechanism by which newly developing T
cells and B cells are rendered non-reactive to self.
- It occurs while cells are still present in the primary lymphoid organs
(thymus and bone-marrow), prior to export into the periphery.
1) Clonal Deletion of immature thymocyte contribute to the elimination of
self-reactive thymocytes.
2) Clonal Inactivation is also a mechanism of central tolerance. T cells
specific for self antigen are present but unresponsive (anergy).
11.3.3 Peripheral Tolerance
- is generated after the cells reach the periphery.
- Self-reactive thymocytes can escape thymic deletion as there are proteins
expressed in peripheral tissues that will not be present in the thymus during
thymocyte selection.
- Regulatory T cells, generated from self-reactive T cells in the thymus
during T cell differentiation, exert their immune suppression in the
periphery on other self-reactive T cells.
Mechanisms of peripheral tolerance
11.3.4 Factors that influence the induction of tolerance
 High level of self-antigen expression ---> clonal deletion ---> Peripheral
tolerance
 Low level of self-antigen expression ---> Ignorance
11.3.5 Induction of tolerance versus immunity
 Two signal model of lymphocyte activation, Bretscher and Cohn (1970).
- Recognition of one antigenic determinant leads to “paralysis”.
- Recognition of two antigenic determinants leads to “induction”.
11.4 Tumor Immunology
11.4.1 Innate Anti-tumor Response
 The cells responsible for innate immunity include the granulocytes
(neutrophils, eosinophils, and basophils), mast cells, natural killer (NK)
cells, a subset of T cells called NKT cells, dendritic cell, and macrophages.
 During the initiation of an immune response, dendritic cells promote NK
cell activation, whereas NK cells influence dendritic cell maturation.
---> may be important in generating an immune response against tumor
growth.
 A reduction in certain MHC class I molecules leads to NK cell-mediated
destruction.
 Tumor cells that have downregulated their surface MHC class I molecules
are targets for NK cell lysis.
 The mechanism of NK cell cytotoxicity is similar to that of CTLs.
 NKT cells regulate both CTL and NK cell anti-tumor activity through
cytokine secretion.
 Evidence suggests that tumors express ligands for stimulatory receptors
on NK and NKT cells that trigger anti-tumor activity.
 NKT cells have been shown to have a role in anti-tumor immunity and
therefore tumor regression, but these cells can also suppress an anti-tumor
response.
11.4.2 Immunosurveillance
 The cytokine INF acts as a tumor surveillance system. There is
enhanced tumor development in the absence of INF.
 NK and NKT cells have been shown to be involved in tumor rejection.
11.4.3 Tumor Antigens
 Tumor antigen is a substance produced in tumor cells that
triggers an immune response in the host.
 Tumor-Specific Antigens are present only on tumor cells.
Tumor-Associated Antigens are present on some tumor cells and
also some normal cells
 Tumor-associated antigens may be encoded by mutant cellular
genes.
 Certain tumor antigens are used as tumor markers.
Tumor antigens can be used in cancer therapy as tumor antigen
vaccines.
Tumor antigens can be classified as;
1.
2.
3.
4.
5.
6.
7.
Products of Mutated Oncogenes and Tumor Suppressor Genes
Products of Other Mutated Genes
Overexpressed or Aberrantly Expressed Cellular Proteins
Tumor Antigens Produced by Oncogenic Viruses
Oncofetal Antigens
Altered Cell Surface Glycolipids and Glycoproteins
Cell Type-Specific Differentiation Antigens
11.5 Induction of Tumor Immunity
 Cancer Immunotherapy is the use of the immune system to reject
cancer.
 Cross presentation of exogenous tumor antigen by bone marrow-derived
cells is necessary for presentation of MHC class I restricted tumor antigens
and activation of CTLs against tumor antigens.
 The ineffective anti-tumor responses may be due to;
1) limited cross presentation of tumor antigen
2) limited activation of sufficient numbers of CTLs in the lymph nodes.
11.5.1 Boosting the immune system
 Boosting the immune system involves modulating costimulation and
dendritic cells.
1) CD40 ligation on dendritic cells is required for the development of an
anti-tumor immune response.
2) Modulating costimulatory signals on T cells has the potential to stimulate
anti-tumor immunity.
----> Costimulatory signal = CD28 on T cell
----> B7 = ligand of CD28
11.5.2 Evasion of Immunity by tumors
1) Tumor cells downregulate the expression of MHC class I molecules.
2) Some antigenic epitopes are lost as the tumor progresses.
3) Tumors may also secrete immunosuppressive cytokines such as TGF-
and IL-10, which can decrease cell-mediated immune response.
4) CD4+CD25+ regulatory T cells appear to suppress the activation of CD4+
T cells and CD8+ T cells.
11.5.3 Vaccination with Dendritic cells
 Inoculation with dendritic cells exposed to tumor antigens can lead to
tumor-specific protection in naïve animals in different experimental
systems.
----> induction of effective anti-tumor CTL responses.