Immunological aspect of tumor

Ahmad Shihada Silmi

Hematologist & Immunologist

IUG

Definition

A tumor erupts as a result of a mutation or damage to one cell leading to abnormal proliferation.

Once a tumor cell has erupted it can be one of the three kinds:

Not viable: the control mechanism of the cell it self discover the mutation & induce apoptosis.

Immunogenic: the mutation is expressed on the cell surface in such a way that the immune defense system recognize it as non-self and induce apoptosis.

Not recognizable: the mutation is expressed on the cell surface so diffusely that the immune defense system recognize as self, thus giving it the opportunity to proliferate.

Four mechanisms of oncogene activity to deregulate cell division

A closer look at p53

Oncogenesis

proto-oncogenes

tumorsuppressorgenes

oncogenes

carcinogenresults in mutation

dysfunctional tumor suppressorgenes

inheriteddefect

increased GF

increased GF receptors

exaggerated response to GF

loss of ability torepair damaged cells or induceapoptosis

Cancer cells are different

Escape normal intercellular communication Allow for rapid growth Increased mobility of cells Invade tissues Metastasis Evade the immune system

Tumors and the Immune System

Clinical tumors, by definition, have been able to evade the immune response

• Deletional Tolerance

• Nondeletional Tolerance

QUESTIONS FOR TUMOR IMMUNOLOGY

What does the immune system target on cancer cells?

What is the antitumor response?

Why is it ineffective?

How can we augment it?

EXPERIMENTAL EVIDENCE FOR TUMOR ANTIGENS AND IMMUNE RESPONSE

Tumor Antigens

a. Tumor specific antigens (TSA)-present on t.c. , not on normal cells.

b. Tumor associated antigens (TAA)-present on t.c.+ some normal cells

Tumor Specific Antigens

1) Mutated tumor cell proteins

2) Tumor-specific mutated oncogenes or tumor suppressor genes

3) Over-expression of normal antigens

4) Viral oncogene expression on surface of the cell

TUMOR OVEREXPRESSION OF NORMAL AG

Tumor Associated Antigens

Human Chorionic Gonadotropin (HCG)

Alpha Fetoprotein (AFP)

Prostate Specific Antigen (PSA)

Mucin CA 125 (glycoprotein molecules on both normal epithelium and carcinomas)

Carcinoembryonic Antigen (CEA)

CEA TUMOR ANTIGEN IN COLON CANCER

0 200 300 400100

Time in Days

CE

A (

ng/

ml)

10

100

1000

Normal Range

Surgical Removal of Tumor

Clinical Manifestations Appear

Tumor Surveillance

Macrophage/Dendritic cell attack or antigen presentation

CD8 cell-mediated cytotoxicity

Antibody dependent cell mediated cytotoxicity (ADCC)

Natural killer cells

immunological surveillance

1) CD8 Tc cells: upon encounter with abnormally expressed self antigen presented on MHC1 molecule, it will induce a cytotoxic response.

2) NK cells: do not have antigen receptor, however, they sense abnormal cell surface marker expression, and upon such encounter it will induce cytotoxic response.

3) Macrophage: It has lectin on their surface, thus giving them the capability to bind

to carbohydrate residues. Tumor cell express high number of carbohydrate residues on their

surface and upon encounter with such a cell, it will induce a humoral response.

4) Cytokines: Produced as a result of the recognition of the tumor cell by one of

the cells above, then binds to cytokine receptors of the tumor cell, thus induce appoptosis.

Tumors can both activate and suppress immunity

Tumors can activate the immune response (ex. expression of foreign antigen with MHCI) or suppress the immune response (activation of T regulatory cells that release IL-10 and TGF) – the balance determines whether the cancer becomes clinically relevant or not

Khong, H. T. et al. Nature Immunology 3, 999 - 1005 (2002)

Basic Tumor Immunosurveillance

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

1) The presence of tumor cells and tumor antigens initiates the release of “danger” cytokines such as IFN and heat shock proteins (HSP).

2) These cause the activation and maturation of dendritic cells such that the present tumor antigens to CD8 and CD4 cells

3) subsequent T cytotoxic destruction of the tumor cells the occurs

MAC

MHC II

MAC

T helper

cell

IL-2

T helper Memory cell

T helper

effectorcell

IL-1 Interferon

Macrophages and dendritic cells can directly attack tumor cells, or more commonly can express exogenous antigens (TSA’s or bits of killed tumor cells) to CD4 cells

Tumor cell or tumor derived antigen

Dendritic and Macrophage Presentation of Tumor Antigen to CD4 Cells

MAC or B cell(APC)

MHC 1

T cytotoxic

cell

Perforins, apoptotic signals

Exogenous antigen

T cytotoxi

cmemory

cells

T cytotoxiceffector

cells

T Cytotoxic Cell Activity in Tumor Surveillance

Cancer Cell

T cytotoxic

cell

Endogenous antigen

MAC

MHC II

MHC IAPC

T helper

cell

T helper 2 cell

IL-2

B Cell

Eosinophil

IL-4 IL-5

T helper Memory cell

T helper

Effectorcell

IL-1

T cytotoxic

cell

T cytotoxi

cmemory

cells

T cytotoxiceffector

cells

Perforins, apoptotic signals

Interferon

1

Cancer Cell

T cytotoxic

cell

Endogenous antigen

Perforins, apoptotic signals

Generally ineffective tumor surveillance, but some ADCC

Tumor antigen or tumor cell

SUMMARY

TARGET CELL

YYMAC OR NK

Antibody-dependent cell-mediated cytotoxicity (ADCC)

Y

NATURAL KILLER CELL

NK

Target cell (infected or cancerous)

Perforin and enzymeskiller activating receptor

Do not recognize tumor cell via antigen specific cell surface receptor, but rather through receptors that recognize loss of expression of MHC I molecules, therefore detect “missing self” common in cancer.

Escape Mechanisms from Immuno Surveillance

1) Conservation of cell-surface marker expression.2) Expression of FcRs: Fc binds to constant region of the

produced antibodies ( and not to the antigen-recognition site), thus preventing the phagocytosis of the cell.

3) Secretion of the carbohydrate residues: prevent recognition by macrophages by occupying the carbohydrate binding sites of the macrophage before actual cell-to-cell contact.

4) Termination of cytokine receptor expression: thus making it impossible for cytokines to bind and induce appoptosis (death).

Lack of MHCI as a tumor escape mechanism

Defects in mechanisms of MHCI production can render cancer cells “invisible” to CD8 cells

Tumors can escape immunity (and immunotherapy) by selecting for resistant clones that have occurred due to genetic instability

Immunoediting of cancer cells

Elimination refers to effective immune surveillance for clones that express TSA

Equilibrium refers to the selection for resistant clones (red)

Escape refers to the rapid proliferation of resistant clones in the immunocompetent host

1 (Tumor cell production of immune suppressants such as TGF-, 2) T regulatory cell stimulation with production of immune suppressants such as TGF-

1 2

Avoidance of tumor surveillance through release of immune suppressants

Mapara Journal of Clinical Oncology. 22(6):1136-51, 2004

Tumor cells induce apoptosis in T lymphocytes via FAS activation

1) Cancer cells express FAS ligand

2) Bind to FAS receptor on T lymphocytes leading to apoptosis

TUMOR ESCAPE MECHANISMS

T regulatory cells

Or kill them

Or T regulatory cells

Failure of Immune Response Against Tumor

An effective tumor response to tumor can be hampered by the following factors: if effector cells exist and tumors are antigenic,why aren’t tumors rejected?)

a. Site of tumor. Some tumors arise in areas not accessible to effector cells (eye and central nervous system).

b. Antigenic modulation. Tumor cells may undergo several antigenic changes.

c. Blocking factors. Immune complexes and cytophilic antibodies can mask surface tumor antigens or prevent binding by effector cells or lytic antibodies.

Antitumour Immunotherapy

A. Tumor cell vaccines - some patients have circulating T cells directed against their tumor cells, and in this setting the aim is to increase their frequency.

Autologous or allogeneic tumor cells, x-

irradiated to prevent replication in vivo, or mixed with an adjuvant to increase immunogenicity have been tried.

B. Immunization with tumor-specific peptides - Appropriate only for those tumors for which TAA have been cloned and peptides synthesized. Thus, presently of limited value clinically as vaccines to induce anti-tumor responses.

C. Cytokine therapy - The aim is to augment the antitumor response by increasing the levels of particular cytokines. Among those that have been tried are IL-2, IFN, GM-CSF, IL-7 and IL-12. Problems are the short half-life, toxicity, and non-specificity of cytokines.

D. Monoclonal antibodies - Have been used to deliver immunotoxins, radioisotopes, or chemotherapeutic drugs to tumor cells. New approaches utilize bivalent antibodies containing one arm that recognizes a T cell and another that recognizes a TAA as a means to bring T cells directly to the tumor site.

E. Gene therapy - Combines the concepts underlying tumor cell vaccines with those underlying cytokine therapy or to break tolerance. This is accomplished by expressing genes coding for cytokines, costimulatory molecules, or MHC molecules.

F. Adoptive immunotherapy with antitumor T cells, tumor-infiltrating lymphocytes (TIL), or lymphokine-activated killer (LAK) cells - Problems include difficulties in growing the large numbers of cells required, loss of antigenic specificity for T cells, or an altered homing pattern following reinfusion.

Immunodiagnosis

• Abs directed against tumor Ags are used in immuno-histochemical analysis of frozen sections sampled from cancer patients.

• Analysis of blood for tumor markers such as - fetoprotein in hepatic carcinoma, carcino-embrionic antigen in colonic carcinoma has provided valuable diagnostic information.

• Abs are being used in the imaging of tumor tissues, using radio-opaque substances linked to a tumor specific Ab.