immune disordes: cancer, prof. mohamed labib salem

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