Tumourclasss
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Transcript of Tumourclasss
Tumor
• A tumor is a local growth of abnormal tissue consisting of genetic-altered transformed cells and a number of other cell types and connective tissue components characteristic of each tumor type.
A fight between immune cells and cancer
But, sometimes we lose
How does cancer arise? How does cancer arise? IIII
Q: What causes dysregulated cell growth & proliferation?
• Intrinsic factors - Genetic mutations on Oncogenes & Tumor suppressor genes
• Environmental factors – Radiation, Carcinogens
• Microbial infections – Viruses (viral oncogenes)
Bacteria
How do cancer cells differ from normal?
• Clonal in origin
• Deregulated growth and lifespan
• Altered tissue affinity
• Resistance to control via apoptotic signals
• Change in surface phenotype and markers
• Structural and biochemical changes
• Presence of tumour-specific antigens
Molecular Basis of Cancer
Molecular Basis of Cancer
Uncontrolled cell growth
Conversion of proto-oncogenes to oncogenes: • amplification of c-erbB2 in breast cancer• point mutation of c-ras in kidney and bladder cancers• chromosome translocation of c-myc in Burkitt’s lymphoma
Altered tumor-suppressor genes:• P53 mutation in prostate cancer: failure in cell cycle arrest or apoptosis of prostate tumors• Rb mutation: fail to prevent mitosis
Cell GrowthCell Growth
Control of cell growth
Growth-promotingProto-oncogenes
Growth-restrictingTumor-suppressor genes
Tumor Immunology
• Cancer immunosurveilance: immune system can recognize and
destroy nascent transformed cells
• Cancer immunoediting: immune system kill and also induce
changes in the tumor resulting in tumor escape and recurrence (epigenetic changes or Darwinian selection)
Discovery of Immune
surveillance of tumors1. Immune Surveillance-
Macfarlane Burnet in 1950s
2. Use syngeneic mouse strain => Transplantation exp
3. Immunization w/ irradiated tumor X cells protects a syngeneic mouse w/ live X
tumor cells but not Y tumor cells.
4. Antigens expressed by tumors, termed tumor antigens.
5. Defense against tumors is mainly mediated by T cells
Key Concepts in Tumor immunity
1. Tumors express Ags that are recognized as foreign by the host immune system.
2. Immune responses frequently fail to prevent the growth of tumors.
3. The immune system can be activated by external stimuli to effectively kill tumor cells and eradicate tumors.
4. Various strategies have been developing to enhance the
anti-tumor immune responses.
Immune Recognition of Tumor
Antibodies recognize intact antigens while T cells recognize processed antigens associated with MHC
Examples of tumor antigens-I
Examples of tumor antigens-II
Tumor antigens arise by point mutations in self
proteins
Tumor antigens arise by reactivated genes or overexpressed genes
Immune responses to tumors
1. Adaptive immune responses to tumors: a. CD8 CTLs are the key players on the killing effect of tumors. b. CD4 T helper cells => cytokines => CTLs c. Abs => activating complements or Ab-dep cell-med
toxicity => preventing oncogenic viruses
2. Innate immune responses to tumors: a. NK cells kill many types of tumor cells that have
reduced class-I but express ligands for activating NK cells.
b. Macrophages => Ab-med phagocytosis => Cytokines (TNF-a), ROS, & NO
IInduction nduction of of T cell responses to T cell responses to tumortumorss
Cross-priming (cross-presentation) mediated by APCs, ex. DCs
Direct CTL / NK attack
CTL
TUMOUR CELL
Fas (CD95)
FasLTCR
Class I + Ag
Perforin Granzyme B
Antigen-specific tumor killing:
B cells (opsinization & ADCC)
sIg
Tumor
ComplementMacrophage/opsinization
FcRFabFcNK cells & ADCC
Tumor
Antigen-specific Tumor Killing:T Cells
MH
CI
pepti
de
Apoptosis
T cell receptor (TCR)
CD8 Tumor
IFN-Granzyme B
Q: Why tumors still develop in the body if the immune system has the ability to recognize them?
Tumors develop many ways to escape from immune attacks
Tumor and activated T cells
Two major pathways for TCL: Fas-mediated and perforrin-mediated
Mechanisms of Tumor Mechanisms of Tumor evasionevasion
Tumors w/Fas
Treg infiltrating
Down regulation of the MHC class presentation
pathway• Downregulation of MHC class I expression
is frequently seen in human tumors.• Loss of MHC-I as a mechanism for tumor
escape from CTL-mediated elimination (longitudinal study of melanoma patients)
• Five major HLA altered phenotypes found in tumor tissues (Human Immunol. 2000, 61:65)
The five altered The five altered phenotypesphenotypes
Normal A1A2B8B35Cw7Cw4
1. Total loss -2. Haplotype loss A1B8Cw7
3. Locus loss A1A2B8B35
4. Allelic loss A2B8B35Cw7Cw4
5. Compound phenotype A1
(Human Immunol. 2000, 61:65)
Resistance to killing
• Defective Fas pathway
• Resistance to Granzyme B
• Fas-L and Neutrophil
Cytotoxic T cells
Innate immunity
Three Es of Immunoediting
CTL
CTL
NKT
NK
CD4
NK CTLCD4
NKCTL
Elimination Equilibrium Escape
Genetic instability / tumour heterogeneity
Immunoediting of Cancer
How does MM evade the immune response?
myeloma cancer cell
Broken up to release antigens
APC
APC recruits CTL specific for myeloma Ag
T
T
T
TT
T cells recognise and destroy other
cancer cells
MM cell release factors which
‘turn off’ T cells
The Strategies for Cancer The Strategies for Cancer TherapyTherapy
The best scenario – Kill all the tumor cells without destroy others in the body
1. Surgery – remove tumor cells & tissues physically 2. Radiotherapy – non-selective, strong side effect3. Chemotherapy - non-selective, strong side effect4. Gene therapy – relatively selective5. Targeted therapy - relatively selective6. Immunotherapy => manipulate an immune
response against tumor cells but not normal cells => quite selective
Tumor vaccines-Targeting DCs
Types of Tumor Vaccines
Immunotherapy with cytokine gene-transfected
tumor cells
Systemic cytokine therapy for tumors
Passive Immunotherapy for tumors
Adoptive cellular therapy
Therapy with Anti-tumor Monoclonal
Abs
Approved Anti-tumor mAb
SUMMARY1. Cancer is a complex and progressive genetic disease.
2. Tumors express Ags that could be recognized by the immune system. But some tumors are weakly immunogenic and the immune system often fails to eradicate them.
3. Cancer from clinical cases usually represents the leading of cancer development over the anti-cancer immune responses.
4. The imperative issue in the field of tumor immunology is
to improve the capability of immune defenses to fight cancer.