2016/ 4 / 18 10:00-12:00

Tumor () v.s. Cancer ()

benign tumor ------------- malignant tumor (cancer)

Tumour immunity: effector response to tumour and role of the
microenvironment

Lancet 2008; 371: 77183

 APC

n Antigen-presenting cells (APC) MHC

antigen
(neutrophil, macrophage, B cells) TCR
n Helper T cells (Th) Th
n Cytotoxic T cells (Tc): Killer
n Natural killer cells (NK): Killer
antibody
n B cells: produce antibody TCR
n Suppressor T cells (Treg cells) Tc B
n Memory cells:
News:
Glycoprotein:

OBI 822/821
 Aims:

I. General features of tumor immunology

II. Tumor antigens
III. Immune responses against tumor
IV. Evasion of immune responses by tumors
V. Tumor vaccines
VI. Immunotherapy for tumors
I. General features of tumor
immunology
n Tumor express antigens that are recognized as
foreign by the immune system of the tumor-bearing
host
II. Tumor antigens
n Immune responses frequently fail to prevent the
growth of tumors
III. Immune responses to tumor
VI. Evasion of immune responses by tumors
n The immune system can be activated by external
stimuli to effectively kill tumor cells and eradicate
tumor
V. Tumor vaccines
VI. Immunotherapy for tumors
* Experimental demonstration of tumor immunity

Transplanted live tumor cells tumor

Killed tumor cells for challenge growth

MCA-sarcoma A MCA-sarcoma A -

MCA-sarcoma A MCA-sarcoma B +

*MCA: methylcholanthrene (carcinogen)

II. Tumor antigens
n Tumor-specific transplantation antigen (TSTA):
Tumor antigen that are expressed on tumor cells but
not on normal cells
n Tumor-associated transplantation antigen (TATA):
Tumor antigen that are also expressed on normal cells
1. How to identify tumor antigens?

2. Classification of tumor antigens

1. How to identify tumor antigens?

n Molecular biology:
1-1 mRNA: hybridization, microarray ()
1-2 Protein: proteomics ()

n Immune assay:
1-3 to isolate tumor peptide (epitope)
1-4 to increase the activity of tumor specific
T cells
1-1 mRNA : microarray ()()
1-2 Protein: proteomics ()
1-3 to isolate tumor peptide (epitope)
1-4 Identification of tumor antigens recognized
by T lymphocytes
 2. Classification of tumor antigens

2-1 Products of mutated oncogenes and tumor

suppressor genes
2-2 Products of other mutated gene
2-3 Overexpressed and abnormally expressed
cellular proteins
2-4 Encoded by genomes of oncogenic viruses
2-5 Oncofetal antigens
2-6 Altered Glycolipid and glycoprotein antigens
2-7 Tissue-specific differentiation antigens
* Types of tumor antigens

, Rb

n Table 17-1

(CEA)

(PSA)
2-1
 2-4 oncogenic viruses

n DNA oncogenic viruses:

n : Epstein Barr virus (EBV)
n : Human papiloma virus (HPV)()
n : Hepatitis B virus (B)

n RNA oncogenic virus:

n : Hepatitis C virus (C)
n : Human T-cell leukemia virus type I (HTLV-1)
(T)
Activities of selected EBV proteins
2-5 Oncofetal
antigens
* II summary: Types of tumor antigens
recognized by T cells

n Fig. 17-2
III. Immune responses
against tumor
Induction of immunity against tumor cells
induced by polyoma virus (PV)
 1. Humoral immunity directed against
tumor-associated antigens

Humoral Immunity Directed against Tumor-Associated Antigens As

Potential Biomarkers for the Early Diagnosis of Cancer
Hailing Lu,* Vivian Goodell, and Mary L. Disis
Journal of Proteome Research 2008, 7, 13881394
2 .Induction of T cell responses to tumor

n Fig. 17-3
3. Other immune cells mediated with
tumor rejection

CIK cells: cytokine

induced killer cells
IV. Evasion of immune
responses by tumors
1. Down-regulation of MHC class I
expression

+IFN-g
2. Tumor lose expression of antigen
-- when culture with tumor specific T cells, such
antigen loss variant are common in rapidly
growing tumors

3. Tumor cells do not express

costimulators or MHC class II molecules
-- e.g. B7-1 (CD80), B7-2 (CD86)
4. The products of tumor cells may
suppress anti-tumor immune responses
n IL-10
n Transforming growth factor-b
n Fas ligand (Fas L)

5. The cell surface antigens of tumors

may be hidden from the immune system
by glycocalyx molecules
 6. Tumor antigens may induce specific
immunologic tolerance
n Neonatal tolerance:
Neonatal mice + mouse mammary tumor virus
carrier tumor
n Self antigen:
Transgenic (SV40 T antigen) mice
infect SV40 virus tumor
n induce T cell tolerance
Enhance B7:CTLA-4 interaction
*IV Summary: Mechanism by which tumors
escape immune defenses
V. Tumor vaccines prevention

n Fig 17-5
n Successful viral tumor vaccine:

Viral tumor vaccine cancer

Human HBV HCC
Cat Feline hemotologic
leukemia maliganant
virus tumor
Chicken Herpesvirus lymphoma
n T17-2
 VI. Immunotherapy for tumors
1. Stimulation with tumor cells and tumor
antigens: as tumor vaccine

2. Nonspecific stimulation of the immune

system:
-- local administration of inflammatory substances:
e.g. BCG mycobacteria
-- systemic treatment with agents that function as
polyclonal activators of lymphocytes:
e.g. low doses of anti-CD3 antibody
3. Manipulation of costimulatory signals

1. Tumor cell + B7 DNA

2. injection of anti-CTLA4 Ab
4. Enhancement of APC activity
1. + cytokines
2. Heat shock protein
+ tumor antigen
5. activated LAK or TIL cells
LAK: lymphokine-activated killer cells

TIL: tumor infiltrated lymphocytes

+ IL-2 or IL-12
 Tumor-destroying activity of LAK cells plus IL-2
6. Cytokine therapy

n Stimulate activation of T cells and NK

cells:
n Interferons
n Tumor necrosis factors (TNF)
n IL-2
n IL-12
n GM-CSF
n
 TNF-a has inhibitory effect on proliferation
of cancer cells
Tumor necrosis factor-a (TNF-a)
- +

normal melanocytes

cancerous
melanoma cells
 * Systemic cytokine therapy for tumors

n T17-4
IFN +
TNF +

IFN: MHC class I increase; NK activity increase

* Immunotherapy with cytokine gene-
transfected tumor cells local cytokine therapy

n T17-3
n F17-6
7. Therapy with anti-tumor antibodies

n T17-5
n Anti-tumor antibody (magic bullets)
1. Humanized Ab
2. Ab-toxin (immunotoxin):
-- Toxin: ricin, diphtheria toxin
-- Radioisotope
-- Anti-tumor drug
3. Anti-idiotype Ab
 How to generate idiotype antibody for treatment
of B-cell lymphoma ?

Inducuction:
opsoniation,
phagocytosis,
and complement-
plus - antibody lysis
to B cell lymphoma
8. combination: surgery + cellular therapy
+ cytokine + ..
9. Inhibite the inhibitors
Suppressive elements Inhibiting the inhibitors

Regulatory T (TReg) cells Blocking TReg cells function (for

example, using denileukin diftitox
to kills CD25+TReg cells, anti-CCL22
reduces trafficking of TReg cells )

Suppressive, dysfunctional DCs Blocking suppressive pathways (

for example, neutrolizing
B7-H1 or B7-H4 )

Suppressive cytokines (IL-10) Blocking potential common

cytokine signalling pathway (for
example, targeting STAT3 and
suppressor of cytokine signalling 1)
Epstein-Barr virus
( g herpesvirinae, human herpesvirus 4)

n Infectious mononucleosis (kissing disease)

n Nasopharyngeal carcinoma ()
n Burkitts lymphoma ()
n B cell lymphomas (in AIDS) (B)
n Hodgkins disease ()
 I. Virus and genome structure
n Linear double stranded DNA, encased
with in nucleocapsid & viral envelope
n Approximately 172 kb pairs
n 0.5kb terminal direct repeat (TR)
n TRs: circular (episomal DNA) formation
Analysis for clonality

BamHI:

Viral protein : eg. BHRF1

II. Model of EBV infection in human
Natural history of EBV infection
n Epithelial cell: primary infection site
n Major envelope glycoprotein gp 350 bind
to C3d receptor (CD21, CR2) on B cell
MHC class II molecule as cofactor
n Memory B cell: reservior of infection
n Lytic phase: about 100 proteins encoded
n Latent gene: about 10 gene expressed
( two types of nontranslated RNA, six
nuclear protein, two membrane proteins)
III. EBV proteins and tumor formation
n EBNA 1: maintain EBV DNA as circular form
n EBNA 2: enhance growth and transformation
of B cell
n EBNA-3: regulate the expression of cellular
gene
n LMP-1: oncogene
n LMP-2: prevent reactivation of EBV infected B
cell
n EBER: oncogenesis, no protein encode
Activities of selected EBV protein
Expression of EBV latent genes in
diseases
IV. Immune response to EBV

Humoral and cellular immunity

Humoral:
Acute phase: viral antigen of lytic phase
membrane antigen (MA), early antigen(EA),
viral capsid antigen (VCA)
Pronounced IgM Ab to autoantigen and
heterophile Ag
Delayed Ab to latent Ag(EBNA)
n Serology

n Little for protective role

Cellular immunity:
n Atypical lymphocytosis in acute

infection
n Regulation of course of virus induced
transformation of B cell in vitro by EBV
specific memory T cell
Evasion of the immune system
n EBNA-1: inhibit its degradation and
antigen presentation
n Modulate immune system:
BCRF1 protein: mimic interleukin-10
BARF1 protein: soluble receptor for
colonies-stimulating factor 1
n Prevention of apoptosis: BHFR1(bcl-2)
LMP-1
V. Epidemiologic factor
n More than 90% adults worldwide are
seropositive
n In US: 50% human in age<5y/o are positive

50-70% freshman of college are positive

n Symptomatic EBV infection: Infectious
mononucleosis increased with age
<10% in children, 20-70% in young adults>
VI. Diseases:
Infectious mononucleosis
n EBV & infectious mononucleosis

Downey cells
 Cancers associated with EBV
n Nasopharyngeal carcinoma ():
n anaplastic or poorly differentiated
n nasopharyngeal carcinoma: 100%
n preinvasive dysplastic lesion:
clonal EBV genome
n EBV specific IgA
n Burkitts lymphoma () :
n endemic Africa
n associated with malaria
or c-myc expression
n Hodgkins disease
() :
monoclonal EBV genome
in Reed-Sternberg cell
n Lymphoproliferative disease (B) :
congenital and acquired immunodeficiency (impaired
T cell immunity, AIDS)
n Other cancer
AIDS and EBV

n AIDS patients: 10-20X circulating EBV

infected B cell as healthy persons
n Oral hairy leukoplakia: active lytic phase
n Lymphoid interstitial pneumonitis
n Non-Hodgkins lymphoma: EBV DNA
100% in CNS lymphoma