Retno Sintowati, dr. MSc.

IMUNOLOGI KANKER

What’s cancer?Immune response against cancerImmunosurveillanceTumor 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 industriLebih 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 kankerImunitas 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 dasar

pengembangan imunoterapi anti kanker.

Ag kankerTSA (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 onkofetalDiekspresikan slm embriogenesis dan perkembangan janin. Disandi oleh gen yg berperan dlm pertumb.cepat sel embrioJg 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 malignaPSA (Prostate Specific Ag) prostat normal, Ca-prostatCEA ( 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 berperanIMUNITAS HUMORAL :

Ab thd Ag kankerAb menghancurkan sel kanker scr :

LangsungBantuan komplemenMelalui 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-β) 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 not need immunoediting to escape from immune attack. Tumours that are induced by viral infection are more likely to fall into the first category; Willimsky and Blankenstein's1 mouse model seems to produce tumours that fall into the second.

Efektor sistem imun humoral dan seluler pada destruksi kanker

A. HUMORAL1. Lisis oleh Ab dan komplemen2. Opsonisasi melalui Ab dan komplemen3. Hilangnya adhesi oleh Ab

B. SELULER1. Destruksi oleh sel CTL/Tc2. Destruksi oleh sel NK3. Destruksi oleh Makrofag

IMUNITAS SELULER THD KANKER1. 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 NKMerup limfosit sitotoksik yg mengenal sel sasaran yg tdk Ag

spesifik dan tdk MHC dependenDiduga fungsi terpenting sel NK adl anti kankerMengekspresikan IgG-R bunuh sel sasaran mell ADCCJuga melalui pelepasan protease, perforin dan granzim.

3. MAKROFAG inisiator dan efektor imun thd kankerMemiliki enzim2 sitotoksik dan melepas mediator oksidatif

(superoksid dan oksida nitrit).Melepas TNF-α awali apoptosis Ekspresikan IgG-RMemakan dan mencerna sel kanker presentasi ke sel CD4+

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

CMI (Cell-mediated Immunity)

The differentiation of CD4+ T cells into Th1 or Th2 cells

determines whether humoral or cell-mediated immunity will predominate

menangani infeksi virus, bakteri intraselular :

mycobacteria, L. monocytogenes eliminasi sel yang mengekspresikan mol.MHC asing (allograft) eliminasi sel yang mengekspresikan antigen tumor

Peran CMI

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-cell’s granules fuse the cancer cell membrane–release PERFORIN-form pores in thecancer cellmembrane -fluid and salts enter -the cancer cell eventually bursts

The killing process(T-cell’s granules fuse the cancer cell membrane–release 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-β) yg mencegah/hambat respons imun.

Mengembangkan varian Ag negatifMemproduksi musin yg menyamarkan/menutupi Ag

kanker.

Cancer cells evationCancer 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-β, 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 ImunTransformasi maligna dpt tjd dg hilangnya ekspresi

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

Contoh :Common ALLKeganasan yg disebabkan virus Herpes virus,

retrovirus, EBVVirus onkogenik gen virus menyisip ke sel host

pertumb sel tak terkontrol, cegah apoptosis.

Imunodiagnosis 2 tujuan :

Menemukan Ag spesifik sel kankerMengukur 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-kankerAb antikankerCMI 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 toksinImunotx 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 α dan γ)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 γ 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