Immunological Aspects of

Malignancy

Edi dharmana
FK UNDIP, Semarang.
 Why Immunology ?

Diagnosis
Host – Tumor Interactions :
Pathology
Therapy
The Cell Cycle

radiation
chemicals
hormones
viruses
Risk Factors for Head and Neck
Cancer
• Tobacco : carcinogens initiate and
promote
• Alcohol : additional promoter
• Viruses : Ebstein-Barr and HSV
• Ionizing radiation : injures cellular
DNA
• Interference with immunity : aging,
malnutrition
 ONCOGENES AND ANTI-ONCOGENES FOUND IN HUMAN
Oncogenes in HNC (Head Neck Cancer)
Oncogens : Roles
Cyclin D1 : products CCND1 leading to cell cycle progresion
PDGF Involved in GLIOMA
erb-B amplified in 36 %
Squamous inCa
cell HNC
EGF / EGFR
erb-B2 : regulates cellsalivary
Breast, growthgland
in response
cancer to EGF and TGFa
N-ras Leukaemias
EGFR overexpressedin 43 to 62 % in HNC
c-myc Breast, lung cancer
Bcl-2 Lymphoma
Abnormalities
MDM2 in Specific Tumor
Antagonist to p53 Suppressor Genes
P53 genes : mutation of p53 gene presents in 35 – 59 % in HNC
P16 / p21 / p27 : p16 mutation presents 19 to 58 % in HNC
Anti-oncogenes p21 expression is shown in 29 to 92 % in HNC
NF-1 Inhibitor of Ras
RB Component of cell cycle clock
p53,16,21 Inhibit Cyclins and CDKs
 ONCOGENES AND ANTI-ONCOGENES FOUND IN HUMAN

Oncogens : Roles
PDGF Involved in GLIOMA
erb-B Squamous cell Ca
erb-B2 Breast, salivary gland cancer
N-ras Leukaemias
c-myc Breast, lung cancer
Bcl-2 Lymphoma
MDM2 Antagonist to p53

Anti-oncogenes
NF-1 Inhibitor of Ras
RB Component of cell cycle clock
p53,16,21 Inhibit Cyclins and CDKs
AGE INVASIVENESS
GENETICS ESCAPE MECHANISM
NUTRITION PATHOGENICITY
ETC. ETC.

HOST TUMOR

ANTI TUMOR PATHOLOGICAL

 Tumor Immunosurveilance
• The hypothesis was firstly proposed by
Thomas and Burnet in 1957.
• Immunosurveilance: the immunological
resistance of the host against the
development of cancer.
• Immune response against tumor takes
place at an early stage in tumor
development-“eradicating the cancer
before it become apparent.”
The Immune System

T
INNATE RESPONSE ANTIGEN SPECIFIC RESPONSE

IgM IL4, IL-5, IL-6,

TGFb
B CD4 B
IL4 Th2

IL1, IL6, TNF

Acute phase
IgE
response

CD4 IFNg IgA

APC Th0
M

IL4 IgG
IL12
IL12
TNFa
Chemotactic CD4
Th1 CD4
Factors Memory
NK
IFNg,
IFNg IFNg IL-2 B
CD8
CTL
Bacteria
Innate immunity MAJOR PROTECT
CYTOKINE AGAINST
Fungi PODUCTS

Viruses
IFN IL-12, IL-18
Fungi IFN-g Intracellular
Th1 pathogens
Cancer

IL-10, TGFb Autoimmunity,

DC T T reg IL-10
TGF-b allergy?
naive
Induced
chronic
infection

IL-4
Helminths Th2 IL-4 Helminths,
5, 13 extracellular
pathogens

IL-4
EOS
Adapted and redrawn from Playfair J. Infection and Immunity 2004
 IFN-g

PAMP IL-12, IL-18 Th1

CYTOKINES
TLR

CD 28
Naïve T
CTLA-4
B7

TCR

MHC II
MAC Th2
IL-4
IL-4
 HLA Human Leucocyte Antigen

DMB DMA DQB DRB

G
DQA DRA TNF B C E A H
F

CD4

CD8
 Weapons of the host
Antibody

Macrophage

Cancer cell
Helper T cell

cytokine
chemokine
NK cell

Dendritic cell Cytotoxic T cell

 NK ( Natural Killer ) Cell
A non-phagocytic cell, kills target by direct contact. Produces perforin (perforates target)
and granzyme (induces apoptosis). Important for defense against viral infection and tumor.
Also pocesses Fc receptor for Antibody dependent cell cytotoxicity (ADCC) killing
mechanism. Unlike CTL (Cytotoxic T cell), the process of target killing is HLA independent)
Also called Killer (K) cell or Large granular lymphocyte (LGL)

NK
Perforin
Granzyme

Infected cell Lethal hits

Lysis
 Cytotoxic T cells
CD8+ T cells: attaching to class I MHC -peptide
complex, they destroy cancer cells by perforating
the membrane with enzymes or by triggering an
apoptotic pathway.

Surface
contact

Release of
enzymes
 Helper T cells

CD4+ T cells: reacting to class II MHC-

peptide complex, they secret cytokines.

Cytotoxic T cell response (Th1 helper

T cells)
Antibody response (Th2 helper T
cells)
 Cytokines
• Regulating the innate immune system: NK cells, macrophages, and neutrophils;
and the adaptive immune system: T and B cells

• IFN- : upregulating MHC class I, tumor antigens, and adhesion molecules;

promoting B and T cells, macrophages, and dendritic cells.

• IL-2 : T cell growth factor that binds to a specific tripartite receptor on

Tcells

• IL-12 : promoting NK and T cell activity, and a growth factor for B cells

• GM-CSF (Granulocyte-monocyte colony stimulating factor ) --reconstituting

Antigen Presenting Cells
 Activation versus suppression of
immunity during tumor progression

Cytokines Tumor
Regression

Activation >
Tumor suppression
T cell

Suppression
> activation

NK cell DC
Tumor
Progression
 The defense of tumor overweighs the anti-
tumor immunity
Cytotoxic CD8 cells
Dendritic cells
Macrophages Antigen/MHC loss
Cytokines T-cell dysfunction
Antibodies Suppressive cytokine
Suppressive T cells
Overweighing effector cells
immunit
y
defense

Balance
 How tumour cells avoid
immunosurveillance
1. Altering Their Characteristics :
Loss/downregulation of MHC class I
Down-regulation, mutation, or loss of tumor antigens
Loss of costimulation
2. Suppressing the Immune Response :
Ineffective signals to CTL
Alteration in cell death receptor signaling
Immunosuppressive cytokine
3. Outpacing the Immune Response: Tumour cells
can simply proliferate so quickly that the immune
response is not fast enough to keep their growth
in check
(1) Loss/down-regulation of HLA
class I (MHC I)
• Total loss: 2 microglobulin mutation,
alteration in antigen processing machinery
• HLA allelic loss: mutations of HLA class I
genes
• HLA-A, B, C locus down-regulation:
alteration of transcriptional factors
(2) Down-regulation, mutation or loss of
tumor antigens

Tumor antigens (TA)

Tumor associated antigen (TAA)

• Complete loss
• Down-modulation
 (3) Loss of costimulation
Costimulatory molecules recognized:
B7.1(CD80)
B7.2(CD86) B7 family
CD40 L
CD27, CD30
4-1BB
OX40
ICAM-1
 (4) Alterations in cell death
receptor signalling
• Defects in Fas/FasL signaling system:
resistance to apoptosis

• Apoptosis resistance: overexpression

of Bcl-2
 (5) Immunosuppressive
cytokines
• a number of immunosuppressive cytokines.
• IL-10 inhibits antigen presentation and IL-12
production.
• TGF-beta induces overproduction of IL-10.
• VEGF (vascular endothelial growth factor),
avoid immune recognition, inhibit the
effector function, prevent T cell activation,
cytokine production.
 (7) Production of other
suppressive factors
• IDO (Indoleamine 2, 3-dioxygenase):
expressed in most human tumour tissues
and splenic DC subsets, leading to
blockage of proliferation of T cells
• ganglioside (sialic acid containing
glycosphingolipids)
• Prostaglandins
 Tumor Immunotherapy

Strategies to improve the tumor-

associated immune response by
either boosting components of the
immune system that produce an
effective immune response or by
inhibiting components that suppress
the immune response.
 Immunotherapy --- Reverse
the imbalance
imm
unity

Tumor Immunotherapy
defe
nse

n se
defe

Tumor Progression
unity
imm
Advantages of Immunotherapy
for cancer
• Tumors are immunogenic
• Single cell kill
• Migrate to tissue
• Memory
• Specific
• Life-long protection
 Main Mechanisms of
Immunotherapy
• Stimulating the antitumor response, either by increasing
the number of effector cells or by producing soluble
mediators.

• Decreasing suppressor mechanisms.

• Altering tumor cells to increase their immunogenicity and

make them more susceptible to immunologic defenses.

• Improving tolerance to cytotoxic drugs or radiotherapy,

such as stimulating bone marrow function with GM-CSF.
 Current Immunotherapeutic
strategies in clinic or clinical trials
• Antibody Therapy
• Cytokine Therapy
• Adoptive Therapy
• Vaccination
• Gene therapy
• Combinational therapy
 Adoptive immunotherapy
• Stimulating immune cells by exposing
them to tumour cells or antigens in the
laboratory and then injecting expanded
populations of the treated cells into
patients.
• Patient is both donor and recipient.
 Antitumor Vaccines

Administration of some form

of antigen to induce a specific
antitumour immune response.
Antitumor Vaccines
Antitumor Vaccines
 Dendritic Cells That Attack Cancer
Dendritic cell
Complex binds matures and is
to dendritic cell infused back into
precursor patient

Tumor antigen

T cell
Tumor
antigen is
linked to a Complex is
cytokine taken in by
dendritic cell
precursor

Cancer cell

T cells attack cancer cell

 Combinational Therapy
-- a three-stranded cord is not easily broken

• Combination of different immunotherapies

ACT+IL-2 + costimulation

• Combining immunotherapy with other

therapeutic strategies