IMUNOLOGI KANKER

Retno Sintowati, dr. MSc.

Whats cancer?
Immune response against

cancer
Immunosurveillance
Tumor evasion
Immunotherapy

Uncontrolled growth of a single

transformed (malignant) cell

Imbalance of oncogene vs. tumor
supressor gene
Role of environment exposure?

ONE transformed cell Clone of transformed

cells Generate a mass Metastasis

Mortalitas tinggi di negara2 industri

Lebih sering pd org dg supresi sistem

imun (radiasi 100x > berisiko)

Akibat kerusakan dlm mekanisme
molekuler yg mengatur proliferasi dan
homeostasis.
Mutasi/perub genetik transformasi
kemamp melepaskan diri dr
mekanisme regulator kemamp
melepaskan diri dr respons imun.

TUMOR REJECTION
ANTIGEN (TRA)
TSTA = Tumor-Specific Transplantation

Antigen
Peptide of tumor-cell proteins
Not displayed in normal cells
Discriminatemalignant from

normal cells
Specific to individual tumors
Presented by MHC to T-cell

PATHOGENESIS OF TRA
TRA may arise by pointmutations in a

self proteinduring oncogenesis

Antigen kanker
Imunitas kanker : proteksi sistem imun

thd timbulnya kanker.

Respons imun alamiah thd kanker jk
kanker mengekspresikan Ag
imunogenik.
Misal : kanker yg diinduksi virus
onkogenik akan mengekspresikan Ag
virus di permukaan selnya.
Ag kanker yg unik mrpk sasaran yg
dpt dikenali sist imun utk kmdn
dihancurkan.
Identifikasi molekuler Ag kanker

Ag kanker
TSA (Tumor Specific Ag)
Mrpk Ag sasaran ideal utk Tx imun

kanker.
Misal: Protein yg diprod akibat mutasi
1/> gen, protein kanker yg diinduksi
virus.
TAA (Tumor Asssociated Ag)
Mrpk Ag yg tdk kanker spesifik.
Dpt dikenal sist imun krn perubahan

jumlah ekspresi profil proteinnya

(kuantitatif).
Misal : Ag onkofetal, Tissue-specific
differentiation Ag (MDA, PSA, AFP).

 Ag onkofetal
Diekspresikan slm embriogenesis dan perkembangan janin.
Disandi oleh gen yg berperan dlm pertumb.cepat sel embrio
Jg diekspresikan oleh testis normal.
Dikenal sbg Ag kanker testis, paru, kepala, leher dan kandung kencing.

Tissue-specific differentiation Ag.

Mrpk protein yg diekspresikan pd sel yg mjd kanker dan

ditemukan terus ssdh transformasi neoplastik

Menunjukkan asal jaringan kanker.
MDA (Melanoma differentiation Ag gp 100) melanoma
maligna
PSA (Prostate Specific Ag) prostat normal, Ca-prostat
CEA ( Carcinoembryonic Ag) kadar > 2,5mg/ml dlm
sirkulasi pd penderita Ca-colon, Ca-pancreas, Ca-pulmo,
Ca-mammae, Ca-gaster
AFP (alfa feto protein) kadar tinggi dlm serum fetus
normal, eritroblastoma testis, hepatoma.

Respons imun terhadap kanker

Imunitas seluler pd kanker lebih banyak berperan
IMUNITAS HUMORAL :
Ab thd Ag kanker
Ab menghancurkan sel kanker scr :
Langsung
Bantuan komplemen
Melalui sel efektor ADCC (sel yg memiliki FcR sel NK dan
Makrofag) opsonisasi atau dg jln mencegah adhesi sel
kanker.
Ab diduga lebih berperan pd sel kanker yg bebas

( leukemia, metastase kanker) dibanding kanker

padat.

The crucial role of dendritic cells, natural killer cells and T cells in the tumour microenvironment.

Proposed functions in tumor immunology. Tumor-associated antigens

(TAAs) and tumor growth factor-beta (TGF-) induce regulatory T-cell

(Treg) expansion in combination with immature dendritic cells (DCs).
Tumor-infiltrating macrophages may secrete interleukin 10 (IL-10),
and IL-10 also may induce Treg expansion. Expanded Tregs suppress the
functions of CTL, NK, and NKT. TAA, tumor-associated antigen; DC,
dendritic cell; NK, natural killer cells; NKT, natural killer T cell; CTL,
CD8+ cytotoxic T lymphocytes

Escaping the immune system a model.

After initial growth, tumours usually shed some
immunogenic material from dead or dying tumour cells.
This debris is picked up by dendritic cells, which
transport it to the lymph node and 'present' it to T cells.
The subsequent immunological events are determined by
the manner in which the tumour is perceived by the
dendritic cell network.
a, If the tumour, apart from shedding debris, also emits
'danger' signals such as stress proteins, the dendritic
cells will be activated. These activated cells present the
tumour debris to the T cells, eliciting a robust response
and causing the T cells to multiply and kill tumour cells.
The only way for tumour cells to survive is to escape by
immunoediting2, 7.
b, If the tumour manages to masquerade as healthy
tissue, giving off no danger signals, the dendritic cells
are not activated. The T cells therefore tolerate the
tumour material presented to them, and do not become
killers9. Tumours capable of such tolerance induction do

Efektor sistem imun humoral dan

seluler pada destruksi kanker
A. HUMORAL
1. Lisis oleh Ab dan komplemen
2. Opsonisasi melalui Ab dan komplemen
3. Hilangnya adhesi oleh Ab

B. SELULER
1. Destruksi oleh sel CTL/Tc
2. Destruksi oleh sel NK
3. Destruksi oleh Makrofag

IMUNITAS SELULER THD KANKER

1. CTL
SEL KANKER MENGEKSPRESIKAN Ag UNIK pacu CTL/Tc spesifik

hancurkan kanker.
CTL mengenal peptida asal TSA yg diikat MHC-I.
CTL tdk sll efisien dan tdk sll terjadi pada kanker.

2. SEL NK
Merup limfosit sitotoksik yg mengenal sel sasaran yg tdk Ag spesifik

dan tdk MHC dependen

Diduga fungsi terpenting sel NK adl anti kanker
Mengekspresikan IgG-R bunuh sel sasaran mell ADCC
Juga melalui pelepasan protease, perforin dan granzim.

3. MAKROFAG inisiator dan efektor imun thd kanker

Memiliki enzim2 sitotoksik dan melepas mediator oksidatif

(superoksid dan oksida nitrit).

Melepas TNF- awali apoptosis
Ekspresikan IgG-R
Memakan dan mencerna sel kanker presentasi ke sel CD4+

CMI (Cell-mediated
Immunity)

merupakan fungsi efektor sel T

mekanisme pertahanan tubuh
terhadap mikro
organisme intraselular fagosit & nonfagosit
sel-sel yang berperan :
- Th CD4+ (Th1)
mengaktifkan fagosit
menginduksi inflamasi
- CTL CD8+
fungsi efektor terhadap sel target yang terinfeksi
di dalam sitosol
- Th2
menurunkan aktivasi makrofag
meningkatkan aktiv. eosinofil dan sel mast

The differentiation of CD4+ T

cells into Th1 or Th2 cells
determines

whether humoral
or cell-mediated
immunity will
predominate

Peran CMI
menangani infeksi virus, bakteri
intraselular :
mycobacteria, L. monocytogenes
eliminasi sel yang
mengekspresikan mol.MHC
asing (allograft)
eliminasi sel yang
mengekspresikan antigen
tumor

THE ROLE OF IMMUNE SURVEILLANCE

Detect & kill the cancer cells

THE ROLE OF IMMUNE SURVEILLANCE

Detect & kill the cancer cells!
NK, CTL, ADCC, apoptosis induction

The killing process(T-cells granules

fuse the cancer cell membranerelease
PERFORIN-form pores in thecancer
cellmembrane -fluid and salts enter
-the cancer cell eventually bursts

THE ROLE OF IMMUNE SURVEILLANCE

Antibody-dependent cell cytotoxic lysis

(ADCC) by NK and CTL

Bila sel kanker memiliki penanda diri,

mengapa kejadian kanker meningkat?

6 Mekanisme bagaimana tumor

melepaskan diri dari respons imun
Kebanyakan sel tumor tdk mpy molekul kostimulatori

(spt B7/CD8+, CD86).

Sedikit/kurang mengekspresikan MHC-I (shg resisten thd
sel Tc).
Mengekspresikan FasL(ligan Fas) memacu apoptosis
sel Tc yg menginfiltrasi jaringan kanker.
Memproduksi berbagai sitokin imunosupresif (misal. TGF) yg mencegah/hambat respons imun.
Mengembangkan varian Ag negatif
Memproduksi musin yg menyamarkan/menutupi Ag
kanker.

Cancer cells evation

Cancer cells are genetically unstable,

lose their antigens by mutation

Loss of MHC class I expression

prevent CD8 Tc recognition
- Brown stain:
HLA class I
expression in
infiltrating
lymphocytes
and tissue
stromal cells
of prostatic
carcinoma.
- Most tumor
cells show no
staining

Mechanisms of immune suppression by malignant

tumors
Malignant tumors can directly induce Treg cell or T-DC
activity via elaboration of several membrane-bound or
secreted cytokines/factors. Treg cells and T-DC can also
modulate each other via similar cytokine interactions.
These suppressor cells or mediators, in turn, inhibit
cytolytic functions of effector T cells (CTLs) or NK cells.
TGF-, which is expressed in both membrane-bound and
soluble forms, can be very critical in most of these
interactions.
CTL: Cytotoxic T lymphocyte; DC: Dendritic cell; NK:
Natural killer; PGE2: Prostaglandin E2; T-DC:
Tolerogenic/suppressor DC; TGF: Transforming growth
factor; Treg: Regulatory T cells.

Keganasan Sistim Imun

Transformasi maligna dpt tjd dg hilangnya ekspresi

MHC-I
meningkatkn potensi metastasis
Menurunkn kemungk. Utk dikenal sel T, tp tdk sel NK

Contoh :
Common ALL
Keganasan yg disebabkan virus Herpes virus,

retrovirus, EBV
Virus onkogenik gen virus menyisip ke sel host
pertumb sel tak terkontrol, cegah apoptosis.

Imunodiagnosis
2 tujuan :
Menemukan Ag spesifik sel kanker
Mengukur respons imun penderita thd sel kanker test reaksi
kulit.
Deteksi sel Ca dan produknya scr imunologik
Protein mieloma Bence-Jones (Ca sel plasma)
AFP (hepatoma)
CEA (Ca GIT)
Deteksi imunologik marker sel kanker yg lain (enzim, hormon)
Deteksi Ag tumor spesifik dlm sirkulasi

Deteksi respons imun anti-kanker

Ab antikanker
CMI antikanker

Terapi kanker
Imunoterapi pasif
mAb tdk spesifik, mis. mAb anti CD20 (CD20 diekspresikan oleh

sel B normal dan sel limfoma)

Imunotoksin mAb thd TAA digab dg toksin
Imunotx aktif
Cegah anergi sel T (anergi tjd jk Ag Ca dipresentasikan ke sel

T tanpa bantuan mol kostimulatori)

Dg cara infuskan sitokin (IL-2, IFN dan )
Lymphokine Activated Killer Cells (sel LAK)
Limfosit perifer dibiakkan dg IL-2 sel NK aktif infuskan lagi ke pasien.

Tumour Infiltrating Lymphocyte (TIL)

Trtm td makrofag dan limfosit NK dan CTL sel CD8+

Macrophag Activated Killer Cells

Monosit dr darah perifer + sitokin IFN sel sitotoksik n fagositik tp non

spesifik.

IMUNOTERAPI
Using the immune response to attack
tumorsMonoclonal antibodiesagainst tumor

IMUNOTERAPI
Transfection of tumours with the gene for
B7 orfor GM-CSF enhances tumor
immunogenicity