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Transcript of Tumor Immunology
Immunology Tumor Transformation Primary Defenses Secondary Defenses CTL Self-MHC I Foreign-MHC I Tumor Cells CTL Death Proliferation of Tumor Same MHC I Tasmania Island Most Detectable Tumors Tumors Caused by Viruses
11.9% Least Detectable Point Mutations Adaptive Immune Response Tumor Specific Antigens
Self proteins via protein splicing Tumor Associated Antigen Somatic gene: Not normally expressed
Expressed when cell becomes tumor
Seen as foreign by body Chemotherapy vs. Radiotherapy Cellular Mechanisms against Cancer
-Main protection based on well-controlled cell division
-Repair of certain types of DNA damage
-To become cancerous, a cell must acquire multiple mutations
-When it is able to form cancer, it has undergone malignant transformation 1890's- Dr. Coley: “Coley’s mixed bacterial toxins" 1950’s- Fould was one of the first to study tumor progression
1953- The Cancer Research Institute
- Goal= find a cure for cancer Ovarian Cancer Chemo-drugs External Beam Machine
(Linear Accelerator) Radiotherapy How is radiation successful against cancer?
Destruction of DNA
Timing of radiation
Post-operative Late 1960's- allogeneic hematopoietic cell transplantation (HCT) was devised as a method to cure cancer. Two classes of genes that contribute to malignant transformation
--Proto-oncogenes- normally contribute positively to the initiation and execution of cell division
Oncogenes- mutant forms of proto-oncogenes
--Tumor suppressor genes- encode proteins that prevent the unwanted proliferation of mutant cells
•Example: p53- responds to DNA damage, causes apoptosis
•Damage to p53 causes cell to lose protective function
•Over 50% of cancers have p53 mutation
-Estimated that 5-6 independent mutations cause a cell to become cancerous- but each cell is unique How Radiation is Given External Beam Radiation
3-dimentional conformal radiation therapy
Internal Radiation (Brachytherapy)
Interstitial, Intracavitary, and Episcleral
Monoclonal antibodies Around 2004 researchers started to develop vaccines that could possibly reduce the risk of cancer. Radiotherapy: Side Effects Healthy cell death
Can somebody become radioactive?
Skin irritation, fatigue, hair loss, and urinary problems
Fibrosis, memory loss, infertility, and possibly new cancer Like viral infections, malignant transformation alters
protein expression in cancer cells in a way that make the
cells appear foreign to the immune system.
Notably, there are changes in expression of MHC class 1
Detected by NK cells and cytotoxic t-cells Tempo Differenes
•In tissues where a barrier is breached, innate and adaptive response is initiated via inflammation.
•Innate immune mechanisms available within hours of the start of infection
•Adaptive available within 2 weeks
•Malignant transformation might go unnoticed by body
•Could be lack of response for years
•Inflammation response begins when healthy tissue begins to be damaged
•Most cases- the body can control and eliminate the cancer at an early stage using immunosurveillance or cancer immunosurveillance (surveying the body for cancer)
•Small minority- the tumor load overwhelms the immune system and is diagnosed as clinical cancer Rituximab
(monoclonal antibody) Non-Hodgkin’s lymphoma (NHL) and chronic lymphocytic leukemia (CLL)
Administered through IV and can take 6 hours
Targets CD20 on normal and malignant B-Cells
Less toxic way to fight NHL
Many people do NOT experience side effects
Vomiting, fatigue, weight gain, muscle or back pain, and numbness, burning, or tingling in hands or feet •Inflammation caused by bacterial infection may induce immune response to tumor
o Feat is used to treat bladder cancer today
o Mycobacterium bovis cells are introduce to bladder
o Unmethylated CpG-containing DNA of the mycobacteria, the ligand for the Toll-like receptor TLR9 gives it the antitumor effect Cancer
Malignant Synonyms/Terms Types Benign tumors
-Ex: Warts Malignant tumors Immune escape of Tumors Genes related to Cancer Immunological Ignorance
Alter tumor cell characteristics
Weaken IR Transformation:
Outpacing the Immune Response -proto-oncogenes
-Tumor Supressor gene Causes
(External/Internal) Rapid proliferation of tumor cells
(high dose tolerance)
Cancer cells expand
Accumulate mutations and new tumor variants
Dangerous to host's IR
Capable of modifying their microenvironment Internal
-Virus Tumors resist IR, modify microenvironment to escape IR Immunological ignorance Immune surveillance
Lack of danger signals- TLR not 'tripped'
(low dose tolerance)
APC not activated
Clone army does not assemble
No evidence sent to LN
Ignorance allows for rapid proliferation of malignant tumor cells What is a tumor? Altering cell characteristics:
Impaired ag presentation Down-regulation, mutation, or loss of tumor antigen
Loss or downregulation of MHC Class 1
Defects in ag processing onto MHC Class 1 molecules Expression of immunosuppressive factors
VEGF (vascular endothelial growth factor)
Inhibits effector function (Signal 3)
Inhibits differentiation of HPC into DC
Promotes Angiogenesis Tumors weaken the immune system:
T-cell defects Suppress internal signal transduction of immune cells
Loss of TCR-CD3 complex
Defects in functionality
Fas-L role reversal
Apoptosis of T-cell
Tumor resistance to apoptosis
Expression of anti-apoptotic molecules TGF-β
Causes overproduction of IL-10
Induces TF Foxp3 to endow a T-reg Sarcoma’s
Myelomas Staphylococcus aureus Name Based on Location in Body Serratia marcesens
In the 1980s specific techniques were developed to better
understand how cancer was linked to specific genes. Doctoring T-cells DNA Sequencing http://chemocare.com/chemotherapy/drug-info/Rituxan.aspx
Marin R, Ruiz-Cabello F, Pedrinaci S, Mendez R, Geraghty DE, Garrido F. 2003.Analysis of HLA-E in human tumours. Immuno- genetics 54(11):767–775.
Benitez R, Godelaine D, Lo pez-Nevot MA, Brasseur F, Marchand M, Cabrera T, VanBaren N, Andry G, Jimenez P, Andry C, Ruiz- Cabello F, Boon T, Garrido F. 1998. Mutations of the b2- microglobulin gene result in a lack of HLA class I molecules on melanoma cells of two patients immunized with MAGE peptides. Tissue Antigens 52:520–524.
Pardoll, D. M. (2001) Immunology. Stress, NK receptors, and immune surveillance Science 294,534-536
Topping K, Fletcher L, Agada F, Alhamarneh O, Stafford N, Greenman J. 2009. Head and neck tummor immunology: basic concepts and new clinical implications. The Journal of Laryngology & Otology 123: 9-18.
Wynberg J, Childs R. 2004. Evolution in Tumor Immunology: Directing Allogeneic Immune Cells Against Metastatic Cancers. Science Communications first quarter: 26-29.
Nowell, Peter. 2002. Tumor progression: a brief historical perspective. Cancer Biology 12: 261-266.
Algarra I, Cabrera T, Garrido F. 2000. The HLA Crossroad in Tumor Immunology. Human Immunology 61: 65-73.
Lowy, Ilana. (1994). Experimental Systems and Clinical Practices: Tumor Immunology and Cancer Immunology, 1895-1980. Journal of History of Biology 27 (3): 403-435.
Involves adding gene sequences from different sources to enable T-cells to produce CARs Helps to pinpoint which genes are the source for certain types of cancers Drawing of Coley's
first bone sarcoma case
treated with his toxins.