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
Discriminate malignant from
normal cells
Specific to individual tumors
Presented by MHC to T-cell
PATHOGENESIS OF TRA
TRA may arise by point mutations in a
self protein during oncogenesis
Antigen kanker
Imunitas kanker : proteksi sistem imun
thd timbulnya kanker.
Respons imun alamiah thd kanker
muncul 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.
 Mekanisme efektor melawan kanker
Imunitas seluler pd kanker lebih banyak berperan
Limfosit T : sebag besar oleh sel T CD8/CTL
SelT CD4 umumnya tdk sitotoksik tp berperan mprod sitokin utk pkemb CTL mjd sel
efektor
Sel T CD4 yg diaktivasi Ag tumor TNF n IFN- sekresi MHC I dan sensitivitas tumor
thd lisis oleh CTL
Sebag kecil tumor mexpresikn MHC II aktifkan sel T CD4 scr langsung
APC prof (DG MHC II) fagositosis sel tumor n presentasi protein tumor ke CD4 CD4
teraktifasi
Sel NK : adalah sel efektor dg sitotoksisitas spontan thd berbagai jenis sel sasaran.
Sel efektor yg tdk memiliki sifat klasik dr Makrofag, granulosit maupun CTL
Sitotoksisitasnya tdk tergantung pd MHC.
Makrofag

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 & non-
fagosit
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?
 Mekanisme tumor melepaskan diri
dari respons imun
Kebanyakan sel tumor tdk mpy molekul kostimulatori (spt B7-1 atau B7-
2/CD8+, CD86) tdk mampu maktivasi CTL.
Sedikit/kurang mengekspresikan MHC-I (shg resisten thd pengenalan oleh sel
Tc).
Memproduksi berbagai sitokin imunosupresif (misal. TGF-/ transforming
growth factor yg mencegah/hambat fungsi Limfosit n Makrofag. Juga IL-10 yg
hambat fx Makrofag
Mengembangkan varian Ag negatif modulasi Ag permukaan (sbg akibat
pengikatan oleh Ab antitumor, atau oleh endositosis atau pelepasan kompleks
Ag-Ab)
Jk modulasi dikarenakan Ab yg tdk mengaktifkan komplemen, mk tumor aka resisren
thd CAA /complement-activating Ab
Ag masking : Ag tumor disembunyikan krn dilapisi musin ( molekul glikokaliks :
mukopolisakarida yg mgd asam sialat).
Atau dg maktifkan sistem koagulasi dan sel tumor bersembunyi dalam kepompong
fibrin
Mengekspresikan FasL(ligan Fas) (hy dikit) memacu apoptosis sel Tc yg
menginfiltrasi jaringan 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