Immunity to tumors General features of tumor immunity

Immunity to tumors

General features of tumor immunity 1. Tumors express antigens that are recognized as foreign by the immune system of the tumor-bearing host. - Histopathologic studies - Experimental demonstration (1950 s) 2. Immune responses frequently fail to prevent the growth of tumors. 3. The immune system can be stimulated to kill tumor cells and eradicate tumors.

Experimental demonstration of tumor immunity

Tumor antigens (continued) 2 -2. Mutant cellular gene products - Somatic mutation의 결과로 어떤 유전자가 변이된 경우 - Tumor suppression에 관여하는 단백질의 mutation 결과로 생성된 것으로, 예를 들면 - Cycline-dependent kinase-4 (CDK-4)의 mutation : Mutation 결과 inhibitor인 p 15 INK-4와 결합능이 감소됨; Melanoma에서 관찰됨 - p 53의 mutation : 세포 성장을 억제하는 작용을 갖고 있는 p 53 단백질 (a tumor suppressor) 유전자의 mutation; Many cancer cell에 관찰됨

Tumor antigens (continued) 2 -3. Tumor antigens encoded by viral gene - 암 세포 중의 일부는 바이러스 감염에 의하여 유도되는 것으 로 추정됨: Burkitt's lymphoma (EBV), T-cell leukemia (HTLV-I), hepatocellular carcinoma (HBV), cervical cancer (papilloma virus) - Virus에 의하여 유도된 암세포에서 나타나는 viral gene product가 암항원으로 발현됨 - 바이러스 유래 암 항원은 immunological cross-reactivity를 보임: 조직이나 동물 종이 다름에도 불구하고 동일한 항원이 발현됨.

Immune responses to tumors 1. T lymphocytes - CD 8+ Cytotoxic T lymphocytes (CTLs) to kill tumor cells - Antigen presenting cells (APCs) and CD 4+ CTLs are required to induce tumor-specific CTLs. - Cross-priming by APCs (Dendritic cells > Macrophages) APC CD 8+ CTLs Phagocytosis APC MHC CTL Tumor cells ing m i r p s s o Cr I C H M II Help Th CTLs recognize tumor antigens associated with MHC class I molecules

Antibodies - Successful only in a few tumors, especially for B cell lineage tumors (B lymphomas) 2. 3. Natural killer cells - NK cells kill many tumor cells, especially cells that have reduced class I MHC class I expression and can escape lysis by CTLs. - Activated by IL-2, IL-12, IFN- - IL-2 activated NK cells are called lymphokine activated killer cells (LAK cells). - TIL cell (tumor infiltrating lymphocytes) 4. Macrophages - IFN- - Direct cytotoxicity - Antibody dependent cell-mediated cytotoxicity (ADCC)

Evasion of immune responses by tumors 1. Down-regulation of MHC class I expression - CTLs can not recognize tumor cells 2. Loss of expression of antigens that elicit immune response 3. Absence of co-stimulators or MHC class II molecules in tumor cells 4. Active suppression of T cell response by tumor products - Production of Transforming growth factor- - Expression of Fas ligand (Fas. L) 5. Induction of specific immune tolerance to tumor antigens 6. Tumor antigens may be hidden from the immune system by glycocalyx molecules such as sialic acid-containing mucopolysaccharides.

Immunodiagnosis of tumors 1. 2. 3. 4. Plasma 세포 종양: Myeloma 단백의 검출 Alpha-fetoprotein 검출 Carcinoembryonic 항원 검출 전립선 특이 항원 (PSA)의 검출

Immunotheraphy for tumors 1. Stimulation of active host immune responses to tumors - Vaccination with tumor cells and tumor lysates - Tumor vaccine - DCs pulsed with tumor antigen DCs transfected with genes for tumor antigen - Peptide vaccine using tumor-specific antigen peptides

Tumor vaccines

2. Augmentation of host immunity to tumors with transfection of the genes for cytokines and co-stimultors - Cytokines : IL-2, IL-4, IFN, TNF, GM-CSF etc - Co-stimulators : B 7, CD 40, etc

Augmentation of host immunity to tumors with transfection of the genes for cytokines and co-stimultors

3. Nonspecific stimulation of the immune system - BCG - Anti-CD 3 m. Ab 4. Adaptive cellular theraphy - LAK cells - TIL cells