Tumor Immunopathology

T. UtoroDepartment of Pathology Gadjah Mada University School of Medicine

Imunitas TumorPaul EhrlichAntigen tumor bukan seluruhnya self antigen sehingga dapat dikenali oleh sistem imunPengenalan imun sel tumor dapat menjadi alat terapi (mekanisma eliminasi tumor)

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

Imunitas terhadap tumorTubuh mempunyai imunitas terhadap tumor, yang dapt dilihat dari observasi klinis dan eksperimentalBanyak sebukan limfosit di sekitar sel tumorEksperimental: terutama pada percobaan inokulasI tumor

Imunitas terhadap tumorBukti yang lain3. Peningkatan insiden tumor pada individu imunodefisiensi4. Secara langsung tampak pada penderita tumor adanya sel T spesifik dan antibodi

TUMOR IMMUNITYNormal cell

Genetic alteration

Neoplastic transformation

Expression of surface antigens

Non-self antigen

Induce tumor surveillance

TUMOR IMMUNITYQuestions:What is the nature of tumor antigensWhat host effector systems may recognize tumor cellsIs antitumor immunity effective against spontaneous neoplasmsCan immune reactions against tumors be exploited for immunotherapy

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

Immunogenicity of TumorsThe transplanted tumor is rejected because of immunity acquired as a result of the first tumor transplant.

Tumor antigenTwo broad categories:TSAs (Tumor Spesific Antigens)TAAs (Tumor Associated Antigens)

Tumor antigensTSAs (Tumor Specific Antigens)Present only on tumor cells not on any normal counterpart cellsDerived 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

Tumor antigenTSA (Tumor Spesific Antigen)A. Tissue-specific shared antigenB. Antigen resulting from mutationC. Viral antigenD. OtherTAA (Tissue Associated Antigen)A. Tissue specific antigenB. Overexpressed antigenC. Oncofetal antigenD. Differentiation antigen

Tumor Specific AntigensA.Tissue-specific shared antigenEncoded 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

Tumor Specific AntigensB. Antigen resulting from mutationMutated protooncogene and tumor supressor geneP53, K-ras, CDK4, bcr-c-abl

Tumor Specific AntigensC. Viral antigensAntigens derived from oncogenic virusesE7 protein of HPV-16

Tumor Specific AntigensD. Other Tumor AntigenMucinsMay give rise to tumor specific antigen: cancers derived from pancreas, ovary, breastIn the normal counterpart cells they (the epitopes) are masked by carbohydrateGlycosylation of mucins generate epitopesFor practical purposes these antigens are TSAThey are belong tu MUC-1

Tissue Associated AntigenA. Tissue specific antigenShared by tumor cells and their normal untransformed counterpartsMelanocytes and melanoma cells both express tyrosinaseIncludes: MART-1, gp100, tyrosinase

Tissue Associated Antigens B. Overexpressed antigenC-erbB2 (neu): overexpressed in 30% of breast and ovarian cancer

Tissue Associated Antigens C. Oncofetal antigensNormally expressed in embryonic tissueAFP: Alpha FetoproteinCEA: Carcinoembryonic antigen

Tissue Associated antigensD. Differentiation antigenPeculiar to the differentiation state at which cancer cells are arrestedCD10 (CALLA expressed by early B cell, B-cell lymphoma and leukemia)PSA (Prostate Specific Antigen)-hCG, expressed by syncitial trophoblast

Antitumor Effector MechanismsADCC

Cellular effectors that mediate immunityCytotoxic T lymphocytesProtective 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 non-immunogenic for T cellsMacrophagesADCC

Inflammatory reaction is correlated with better prognosisIn some tumorsMedullary carcinoma of the breastSeminomaNPCIn general no clear correlation exist

IMMUNE SURVEILLANCEFacts:Increased occurrence of tumorsIn immunodeficient hostCancers occurs in immunocompetent inviduals

Immunosurveillanceis not perfect

IMMUNE SURVEILLANCEKonsep diperluas dari hanya peran protektif pada pertumbuhan tumor efek sistem imun dalam seleksi varian tumorVarian ini yang imunogenisitasnya berkurang mudah lepas dari deteksi imunologik dan rejeksi (immunosurveillance)

Klasifikasi baruProduk dari onkogen mutan dan gena supresor tumorProduk dari gena mutasi yang lainOverekspresi protein selular atau yang di-ekspresikan secara aberanProduk dari virus onkogenikAntigen onkofetalGlikolipid - glikoprotein permukaan sel yang berubahAntigen diferensiasi yang spesifik jenis sel

Klasifikasi baru1. Produk dari onkogen mutan dan gena supresor tumorAntigen 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

Klasifikasi baru: 2. Produk dari gena mutasi yang lainGen yang tak berhubungan tetapi termutasi hewan coba dengan transplatasi tumor antigen transplantasi spesifikIni potensial masuk ke MHC Kelas I CTLDalam eksperimen banyak ditemuka pada tumor yang diinduksi dengan karsinogen kimiawi atau radiasi

Klasifikasi baru: 3. Overekspresi protein selular atau yang di-ekspresikan secara aberanGen normal ada pada sel counterpart diekspresi berlebihan pada sel tumor respon imun : tyrosinase (enzim biosintesis melanin dalam melasnosit normal dan melanomaMAGE genes

Klasifikasi baru:4. Produk dari virus onkogenikInfeksi virus insersi genom sel inang ekspresi protein baru MHC kelas I CTLHBV, EBV

Klasifikasi baru:5. Antigen onkofetalAntigen yang diekspresikan dalam kadar tinggi dalam tumor dan jaringan fetal, tidak dalam jaringan dewasaCEA, AFP

Klasifikasi baru: 6. Glikolipid - glikoprotein permukaan sel yang berubahCA-125 & CA-199 kanker ovariumMUC-1 permukaan luminal epitel duktal payudara

Kandidat vaksin antitumor

Klasifikasi baruProduk dari onkogen mutan dan gena supresor tumorProduk dari gena mutasi yang lainOverekspresi protein selular atau yang di-ekspresikan secara aberanProduk dari virus onkogenikAntigen onkofetalGlikolipid - glikoprotein permukaan sel yang berubahAntigen diferensiasi yang spesifik jenis sel

Tumor antigens recognized by CD8+ T cells

Mechanisms by which tumors evade the immune system

Mechanisms to escape from Tumor ImmunosurveillanceSelective outgrowth of antigen-negative variantsLoss or reduced expression of histocompatibility antigens (MHC I)Lack of co-stimulation (CD80, CD86)Immunosuppression- oncogenic agent : ionizing radiation, chemicals- tumor product : TGF-5. Antigen masking: by glycocalyx molecule (sialic acid-containing mucopolysaccharides)6. Apoptosis of cytotoxic T cells

Tumor Markers(Petanda Tumor)Indikator biokimiawi adanya/hadirnya tumor (klinis: molekul yang dapat dideteksi dalam plasma atau cairan tubuh lain)Antigen permukaan selProtein sitoplasmikEnzimHormon

Tumor Markers(Petanda Tumor)Petanda tumor tidak dapat dipakai sebagai modalitas utama dalam diagnosisKegunaan utama: tes lab. untuk mendukung dagnosisManfaat lain: memantau respon terapi, dan menandai kalau ada relaps pada masa follow up

Selected tumor markersHormones Oncofetal antigensIsoenzymesSpecific proteinsMucins and other glycoproteinsNew molecular markers

1. Hormones

Oncofetal Antigens

Isoenzymes

4. Specific proteins

5. Mucins and other glycoproteins

6. New molecular markers