Tumor Immunopathology

T. Utoro
Department of Pathology
Gadjah Mada University School of Medicine

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Imunitas Tumor
Paul Ehrlich
Antigen tumor bukan seluruhnya self
antigen sehingga dapat dikenali oleh
sistem imun
Pengenalan imun sel tumor dapat menjadi
alat terapi (mekanisma eliminasi tumor)

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Imunitas Tumor
Lewis Thomas & Macfarlane Burnet
Menamakan pernyatan Ehrlich sebagai
immune surveillance fungsi normal
sistem imun adalah survai seluruh badan
untuk menanggulangi kalau ada tumor
muncul

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Imunitas terhadap tumor

Tubuh mempunyai imunitas terhadap
tumor, yang dapt dilihat dari
observasi klinis dan eksperimental
Banyak sebukan limfosit di sekitar sel
tumor
Eksperimental: terutama pada percobaan
inokulasI tumor
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Imunitas terhadap tumor

Bukti yang lain
3. Peningkatan insiden tumor pada
individu imunodefisiensi
4. Secara langsung tampak pada
penderita tumor adanya sel T
spesifik dan antibodi

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TUMOR IMMUNITY
Normal cell
Genetic alteration
Neoplastic transformation
Expression of surface antigens
Non-self antigen
Induce tumor surveillance
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TUMOR IMMUNITY
Questions:
1. What is the nature of tumor antigens
2. What host effector systems may recognize
tumor cells
3. Is antitumor immunity effective against
spontaneous neoplasms
4. Can immune reactions against tumors be
exploited for immunotherapy

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Tumor antigen
Tumor antigenicity is usually assessed by:
The ability of an animal to resist a live tumor
implant after previous immunization with live or
killed tumor cells
The ability of tumor free host animals to resist
challenge when infused with sensitized T cells
from a tumor-immunized syngeneic donor
The demonstration in vitro of tumor cells
destruction by cytotoxic CD8+ T cells derived
from a tumor-immunized animal
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Immunogenicity
of Tumors

The transplanted tumor is rejected

because of immunity acquired as a
result of the first tumor transplant.

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Tumor antigen
Two broad categories:

TSAs (Tumor Spesific Antigens)

TAAs (Tumor Associated Antigens)

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Tumor antigens
TSAs (Tumor Specific Antigens)
Present only on tumor cells not on any
normal counterpart cells
Derived from peptides that are uniquely
present within tumor cells and presented
on the cell surface by class I MHC
molecules evoke a cytotoxic cell
response
TAAs (Tumor Associated Antigens)
Present on tumor cells as well as on some
normal counterpart cells
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Tumor antigen
TSA (Tumor Spesific Antigen)
A. Tissue-specific shared antigen
B. Antigen resulting from
mutation
C. Viral antigen
D. Other
TAA (Tissue Associated Antigen)
A. Tissue specific antigen
B. Overexpressed antigen
C. Oncofetal antigen
D. Differentiation antigen
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Tumor Specific Antigens

A.Tissue-specific shared antigen

Encoded by genes that are silent in virtually all normal adult tissues
- but expressed in a number of tumors of various histologic types
- Testis (no HLA): the only normal organ in which MAGE protein are
present cannot be expressed on their cell surface
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Tumor Specific Antigens

B. Antigen resulting from mutation

Mutated protooncogene and tumor supressor gene

P53, K-ras, CDK4, bcr-c-abl
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Tumor Specific Antigens

C. Viral antigens

Antigens derived from oncogenic viruses

E7 protein of HPV-16
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Tumor Specific Antigens

D. Other Tumor Antigen

Mucins
May give rise to tumor specific antigen: cancers derived
from pancreas, ovary, breast
In the normal counterpart cells they (the epitopes) are
masked by carbohydrate
Glycosylation of mucins generate epitopes
For practical purposes these antigens are TSA
They are belong tu MUC-1

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Tissue Associated Antigen

A. Tissue specific antigen

Shared by tumor cells and their normal

untransformed counterparts
Melanocytes and melanoma cells both express
tyrosinase
Includes: MART-1, gp100, tyrosinase
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Tissue Associated Antigens

B. Overexpressed antigen

C-erbB2 (neu): overexpressed in

30% of breast and ovarian cancer
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Tissue Associated Antigens

C. Oncofetal antigens
Normally expressed in
embryonic tissue
AFP: Alpha Fetoprotein
CEA: Carcinoembryonic
antigen

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Tissue Associated antigens

D. Differentiation antigen
Peculiar to the differentiation state at
which cancer cells are arrested
CD10 (CALLA expressed by early B
cell, B-cell lymphoma and leukemia)
PSA (Prostate Specific Antigen)
-hCG, expressed by syncitial
trophoblast
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Antitumor Effector Mechanisms

ADCC

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Cellular effectors that mediate

immunity
Cytotoxic T lymphocytes
Protective role against virus-associated tumors
EBV, HPV (possessing MHC class 1)
Natural killer cells (NK cells)
Lymphocytes capable of destroying tumor cells
without prior sensitization (after activation with
IL-2), including many that appear nonimmunogenic for T cells
Macrophages
ADCC
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Inflammatory reaction is
correlated with better prognosis
In some tumors
Medullary carcinoma of the breast
Seminoma
NPC

In general no clear correlation exist

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IMMUNE SURVEILLANCE
Facts:
Increased occurrence of tumors
In immunodeficient host
Cancers occurs in immunocompetent inviduals

Immunosurveillance
is not perfect
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IMMUNE SURVEILLANCE
Konsep diperluas dari hanya peran
protektif pada pertumbuhan tumor
efek sistem imun dalam seleksi varian
tumor
Varian ini yang imunogenisitasnya
berkurang mudah lepas dari deteksi
imunologik dan rejeksi
(immunosurveillance)
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Klasifikasi baru
1. Produk dari onkogen mutan dan gena
supresor tumor
2. Produk dari gena mutasi yang lain
3. Overekspresi protein selular atau yang diekspresikan secara aberan
4. Produk dari virus onkogenik
5. Antigen onkofetal
6. Glikolipid - glikoprotein permukaan sel
yang berubah
7. Antigen diferensiasi yang spesifik jenis
sel
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Klasifikasi baru

1. Produk dari onkogen mutan

dan gena supresor tumor

Antigen permukaan yang diproduksi dalam

sitosol masuk MHC kelas I dikenali oleh
CTL (CD8+)
Atau masuk MHC II dikenali oleh CD4+
Beberapa pasien: CD8+ & CD4+ dalam
sirkulasi dapat mengenali beberapa protein
dari gen termutasi: RAS, p53, BCR-ABL

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Klasifikasi baru:

2. Produk dari gena mutasi yang

lain
Gen yang tak berhubungan tetapi termutasi
hewan coba dengan transplatasi tumor
antigen transplantasi spesifik
Ini potensial masuk ke MHC Kelas I
CTL
Dalam eksperimen banyak ditemuka pada
tumor yang diinduksi dengan karsinogen
kimiawi atau radiasi
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Klasifikasi baru:

3. Overekspresi protein selular atau

yang di-ekspresikan secara aberan
Gen normal ada pada sel counterpart
diekspresi berlebihan pada sel tumor
respon imun : tyrosinase (enzim
biosintesis melanin dalam melasnosit
normal dan melanoma
MAGE genes

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Klasifikasi baru:

4. Produk dari virus onkogenik

Infeksi virus insersi genom
sel inang ekspresi protein
baru MHC kelas I CTL
HBV, EBV

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Klasifikasi baru:

5. Antigen onkofetal
Antigen yang diekspresikan dalam
kadar tinggi dalam tumor dan
jaringan fetal, tidak dalam jaringan
dewasa
CEA, AFP

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Klasifikasi baru:

6. Glikolipid - glikoprotein
permukaan sel yang berubah
CA-125 & CA-199 kanker ovarium
MUC-1 permukaan luminal epitel
duktal payudara

Kandidat vaksin antitumor

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Klasifikasi baru
1. Produk dari onkogen mutan dan gena
supresor tumor
2. Produk dari gena mutasi yang lain
3. Overekspresi protein selular atau yang diekspresikan secara aberan
4. Produk dari virus onkogenik
5. Antigen onkofetal
6. Glikolipid - glikoprotein permukaan sel
yang berubah
7. Antigen diferensiasi yang spesifik jenis
sel
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Tumor antigens recognized by

CD8+ T cells

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Mechanisms by which tumors

evade the immune system

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Mechanisms to escape from

Tumor Immunosurveillance
1.
2.
3.
4.

5.
6.

Selective outgrowth of antigen-negative variants

Loss or reduced expression of histocompatibility
antigens (MHC I)
Lack of co-stimulation (CD80, CD86)
Immunosuppression
- oncogenic agent : ionizing radiation, chemicals
- tumor product : TGF-
Antigen masking: by glycocalyx molecule (sialic
acid-containing mucopolysaccharides)
Apoptosis of cytotoxic T cells

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Tumor Markers

(Petanda Tumor)
Indikator biokimiawi adanya/hadirnya
tumor (klinis: molekul yang dapat
dideteksi dalam plasma atau cairan
tubuh lain)
Antigen permukaan sel
Protein sitoplasmik
Enzim
Hormon
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Tumor Markers

(Petanda Tumor)
Petanda tumor tidak dapat
dipakai sebagai modalitas utama
dalam diagnosis
Kegunaan utama: tes lab. untuk
mendukung dagnosis
Manfaat lain: memantau respon
terapi, dan menandai kalau ada
relaps pada masa follow up
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Selected tumor markers

1.
2.
3.
4.
5.
6.

Hormones
Oncofetal antigens
Isoenzymes
Specific proteins
Mucins and other glycoproteins
New molecular markers

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1. Hormones
HCG (Human Trophoblastic tumors
Chorionic
Nonseminomatous testicular
Gonadotropin) tumor
Calcitonin

Medullary carcinoma of thyroid

Catecholamine Pheochromocytoma and related

& metabolites tumors
Ectopic
hormones
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Paraneoplastic syndromes
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Oncofetal Antigens
-Fetoprotein

Liver cell cancer,

Nonseminomatous germ cell
tumors of testis

Carcinoembryonic Carcinomas of the colon,

antigen
pancreas, lung, stomach,
and heart

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Isoenzymes
PSA (Prostatic Acid Prostate cancer
Phosphatase)

Neuro-specific
Enolase

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Small cancer of lung

Neuroblastoma

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4. Specific proteins
Immunoglobulins

Multiple myeloma and

other gammopathies

Protein-specific antigen Prostate cancer

and protein-specific
membrane antigen

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5. Mucins and other glycoproteins

CA-125

Ovarian cancer

CA-19-9

Colon cancer
Pancreatic cancer

CA-15-3

Breast cancer

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6. New molecular markers

P53, APC, RAS mutation in stool and Colon
serum
cancer
P53, RAS mutation in stool and
serum

Pancreatic
cancer

P53, RAS mutation in sputum and

serum

Lang
cancer

P53 in urine

Bladder
cancer

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