immune disordes: cancer, prof. mohamed labib salem
TRANSCRIPT
Immune Immune DisordersDisorders
Dr. Mohamed Labib SalemProf. of Immunology
Faculty of ScienceTanta University
2
1st signal
2nd signal
2nd signal
1st signal
1st signal2nd signal
The 3 The 3 signalssignalsin in immune immune responseresponse
Immune DisordersImmune Disorders1. Hypo immunity
Cancer Chemotherapy
2. Hyper immunity Autoimmunity Hypersensitivity (types I, II, III, IV)
3. Failure of immunity Infection (Bacteria-Viruses-Fungus – parasites -
protozoa)
Cancer
What Causes Cancer?Some viruses or bacteria
HeredityDiet
Hormones
RadiationSome chemicals
Causes of Immune disorders
Genes and Cancer
Chromosomes are DNA molecules
Heredity
RadiationChemicals
Viruses
Causes of Immune disorders
DNA Mutation
Additions
Deletions
Normal gene
Single base change
DNA
CT
A G C G A A C TAC
A G G C G C T AAC A C T
A G C T A A C TAC
A G A A C TAC
Causes of Immune disorders
Loss of Normal Growth Control
Cancer cell division
Fourth orlater mutation
Third mutation
Second mutation
First mutation
Uncontrolled growth
Cell Suicide or Apoptosis
Cell damage—no repair
Normal cell division
Different Kinds of Cancer
Lung
Breast (women)
Colon
BladderProstate (men)
Some common sarcomas:FatBone
Muscle
Lymphomas:Lymph nodes
Leukemias:Bloodstream
Some common carcinomas:
Naming Cancers
Prefix Meaningadeno- glandchondro- cartilageerythro- red blood cellhemangio- blood vesselshepato- liverlipo- fatlympho- lymphocytemelano- pigment cellmyelo- bone marrowmyo- muscleosteo- bone
Cancer Prefixes Point to Location
Malignant versus Benign Tumors
Malignant (cancer) cells invade neighboring tissues, enter blood vessels, and metastasize to different sites
Time
Benign (not cancer) tumor cells grow only locally and cannot spread by invasion or metastasis
Invasion and Metastasis
3Cancer cells reinvade and grow at new location
1Cancer cells invade surrounding tissues and blood vessels
2Cancer cells are transported by the circulatory system to distant sites
Cancer stagesCancer stages
Cancer Tends to Involve Multiple MutationsMalignant cells invade neighboring tissues, enter blood vessels, and metastasize to different sites
More mutations, more genetic instability, metastatic disease
Proto-oncogenes mutate to oncogenes
Mutations inactivate DNA repair genes
Cells proliferate
Mutation inactivates suppressor gene
Benign tumor cells grow only locally and cannot spread by invasion or metastasis
Time
Cancer Tends toCorrupt Surrounding EnvironmentGrowth factors = proliferation
Blood vessel
Proteases
Cytokines
Matrix
Fibroblasts, adipocytes
Invasive
Cytokines, proteases = migration & invasion
Immune surveillance/editing of tumors
Anti-tumor immune responses
Effectors that can kill Cancer Antibody
Helper T cell
Natural killer cell
Macrophage
Cytotoxic T cell
Cancer cells
Prof. Mohamed Labib Salem
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Typical Events Essential for Anti-tumor Immunity
Prof. Mohamed Labib Salem
The smart interaction
Immune cells
Cancer Cells
Cancer cellsHost Tumor
microenvironment
Why does cancer Why does cancer therapy fail?therapy fail?
Prof. Mohamed Labib Salem
Melanoma growth Melanoma growth in micein mice
Melanoma metastasis into lung
• Tumor cells originate from self (not foreign)• Tumor favor expansion of Regulatory cells that
inhibit tumor-specific T-cell activities• Downregulation of Ag expression in tumor cells. • Secretion of immunosuppressive factors. • Death-receptors such as CD95 and TRAIL receptor
are mutated or lost entirely.• Secretion of factors that favor emergence of
suppressor immune cells such as Treg cells and myeloid derived suppressorcells
Causes of Failure of Cancer Immunotherapy Intrinsic mechanisms
Causes of Failure of Cancer ImmunotherapyIntrinsic/extrinsic mechanisms
Causes of Failure of Cancer ImmunotherapyExtrinsic mechanisms
• Tumor-specific T cells are absent. • Tumor-reactive immune cells do not
localize to the tumor.• T cells fail to proliferate and persist in
response to tumors. • Emergence and sustainability of suppressor
immune cells such as Treg cells and myeloid derived suppressorcells
Prof. Mohamed Labib Salem
Clinically Un-detectable
LocalizedDisease
AdvancedDisease
1:10,000 T cells 1:50 T cells 1:2 T cells
Dise
ase
Burd
en
Causes of Failure of Cancer Immunotherapy High tumor cells/T cell ratio
Prof. Mohamed Labib Salem
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1 3 5 7 10 14 21 30 60 120
CD8+
T c
ell r
espo
nse
Days Post Vaccination
Rapid expansion Rapidcontraction
Lowmemory
1012
Tumor antigen alone
Tumor antigen + Danger signal
Causes of Failure of Cancer Immunotherapy Rapid contraction of T cells upon vaccination
Prof. Mohamed Labib Salem
Regulatoryimmune cells
Immunity is controlled by the balance between stimulatory/regulatory cells
TregMDSCNKT cellsB cellspDCs
Stimulatory immune cells
Dendritic cellsCD4+ T cellsCD8+ T cellsNK cells
Prof. Mohamed Labib Salem
Tumor-induced Immune Dysfunction
MDSC
IL-10
Arginase
ROS, RNS
IDO: depletes L-tryptophan, results in T cell unresponsiveness
Inhibitory/death R:s
Inhibitory/death receptors:FasL
TGF-β PGE2
ROS, RNS: reactive oxygen species results in T cell un-responsiveness
TGF-β and or IL-10 fromTreg, MDSC, and tumorcells suppress T cells
Treg
IDO
MDSC/DC
Arginase: depletes L-arginine, results in T cell unresponsiveness
Prof. Mohamed Labib Salem
Suppression of anti-tumor immunity by myeloid-derived suppressor cells (MDSC)
Cancer Immunotherapy
Melanoma metastasis into lung
THANK YOUProf. Mohamed Labib Salem