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8/9/2019 Tumor Immunology (1)
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Imm n h r Imm n h r
-------- The battle between immune system and cancersThe battle between immune system and cancers
Dr Kevin Sun
Department of Molecular Medicine &Department of Molecular Medicine &PathologyPathology
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• What is Cancer?• How does cancer occur?
• Current therapeutic strategies for cancers
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Definitions of Cancer Definitions of Cancer
• clones of cells that are capable of
.
• Cancer cells arise from host cells vianeoplastic transformation or carcinogenesis.
• Ph sical chemical and biolo ical a entsmay cause cancer. -- carcinogens
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Carcino ensCarcino ens• Radiation: Ultraviolet light, sunshine; X-rays,
radioactive elements induce DNA damage andchromosome brakes.
• Chemical: smoke and tar, countless chemicals
• Oncogenic viruses: insert DNA or cDNA copies
cells.• y: .
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Neoplastic TransformationNeoplastic Transformation---- CarcinogenesisCarcinogenesis
• Activate growth regulatory genes : Growth factorreceptors (erbA, -B, fims, neu); molecules of signaltransduction (src, abl, ras); transcription factors (jun,fos ,myc)- referred to as oncogenes.
• Genes that inhibit growth: (p53 controls DNA repairan ce pro era on; -suppressor oncogenes.
• enes a regu a e apop os s: c - , ax, .
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,
mucous membranes, epithelial cells in glands , . .
liposarcoma, fibrosarcoma’ ’- , - , ,
lymphomas; - solid tumors ,
myeloid, acute and chronic
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cancerscancers
• ec an cs -- surgery,• Physics -- radiotherapy, 1896
• Chemistry -- chemotherapy, 1942• -- ,
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for cancer for cancer
• Cancer cells are immunogenic• Single cell kill
• Memory• Specific
• -
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Cancer Immunolo andCancer Immunolo andImmunotherapyImmunotherapy
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• How does the immune system eliminate cancer cells?
• How can we help to win the battle between immune
sys em an cancers – ancer mmuno erapy• Examples
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• e ypo es s was rs propose y r c n
1909, and modified by Thomas and Burnet in
• Immunosurveilance: the immunologicalresistance of the host against the development of
cancer.• Now referred to “cancer immunoediting”,
and escape.
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Cells of the Immune SystemBone graft
Macrophage
Eosinophil
Mast cell
Basophil
Monoc te
Marrow
Hematopoieticstem cell
Bone
Multipotentialstem cellNeutrophil
Myeloidprogenitor
cell
ate ets
Lymphoid progenitor cell
T lymphocyte en r c ce
Natural killer cellB lymphocyte
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Army of the host to fight cancersArmy of the host to fight cancers
Antibody
Macrophage
Cancer cellHelper T cell
cytokine
chemokineNK cell
Cytotoxic T cellDendritic cell
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CD8+ T cells: attaching to class I MHC -peptide complex, they destroy cancer cells
enzymes or by triggering an apoptotic.
Surface
contactRelease ofenzymes
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CD4+ T cells: reacting to class II MHC-
e tide com lex the secret c tokines.cytotoxic T cell response (Th1 helper T cells)
Logistics force
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The professional antigen-presenting cells In the
na common pa way or ac va ng na ve
cells.Dendriticcell
T cell
-- ar y arn ng rcra
A novel subset of dendritic cells [IFN-producing killer DC] (IKDC):TRAIL& erforin- tumor cell l sis via T cell IFN -an io enesis
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,
NKT cells: TRAIL/perforin- tumor cell lysis;IFNγ-angiogenesis
NK cell NKT cellacrop age
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• Regulating the innate immune system: NK cells,,
system: T and B cells• - -- , ,
adhesion molecules; promoting activity of B and T cells,macrophages, and dendritic cells.
• IL-2 -- T cell growth factor that binds to a specific tripartitereceptor on T cells.- – ,
for B cells
• GM-CSF Granuloc te-monoc te colon stimulatin factor --reconstituting antigen-presenting cells.
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Antibody Antibody -- produced by B cellsproduced by B cells• Direct attack : blocking growth factor receptors, arresting
proliferation of tumor cells, or inducing apoptosis.-- is not usually sufficient to completely protect the body.
• Indirect attack : -- major protective efforts1 ADCC antibod -de endent cell mediated c totoxicit -- recruiting cells that have cytotoxicity, such as monocytes and
macrophages.
-- binding to receptor, initiating the complement system,'complement cascade’, resulting in a membrane attack
, .
Heavy chain
Antigen-binding
region
-- missileAssembled antibody molecule
Constant region
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Tumor elimination
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cancer cell
Escape
Advanced cancer
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CancerCancer
mmuno ogy mmuno erapymmuno ogy mmuno erapy• How does the immune system eliminate cancer cells?
• How can we help to win the battle between immunesys em an cancers – ancer mmuno erapy
• Examples
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Mechanisms of cancer escape from
. er ng e r arac er s cs :Loss/downregulation of MHC class I
- , ,Loss of costimulation
2. Suppressing the Immune Response :
ineffective signals to CTL Alteration in cell death receptor signalingmmunosuppress ve cy o ne
3. Outpacing the Immune Response: Tumour cellscan sim l roliferate so uickl that the immuneresponse is not fast enough to keep their growthin check
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(1) Loss/down(1) Loss/down- -regulation of HLAregulation of HLAclass I (MHC I)class I (MHC I)
• Total loss: 2 microglobulin mutation, alteration in
antigen processing machinery• Haplotype loss: LOH in chromosome 6
• HLA allelic loss: mutations of HLA class I enes
• HLA-A, B, C locus down-regulation: alteration of
• Compound phenotype: 2 or more independentmec an sms
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(2) Down(2) Down- -regulation, mutation or loss ofregulation, mutation or loss of
tumor antigenstumor antigens
Tumor antigens (TA)Tumor associated antigen (TAA)
• Complete loss• Down-modulation
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Tumor Anti ensTumor Anti ens• Altered self: K-ras, products of normally unexpressed
, , ,reading frame, - of post-translational modification, -
different orders of l cos lation mucin-CA125 MUC1 .• Viral antigens: EBNA, E-6,E-7, papilloma virus antigens
of cervical carcinomas.
• Oncofetal antigens : alpha-fetoprotein (AFP),Carcinoembryonic antigen (CEA)• - - ,
leukemias; HER-2/neu epidermal growth factor receptor-
breast cancer (Herceptin).
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.B7.2(CD86) B7 family
CD27, CD30
-OX40
-
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receptor signallingreceptor signalling
• resistance to apoptosis
• Apoptosis resistance: overexpressionof Bcl-2
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(5) Immunosuppressive(5) Immunosuppressive
cytokinescytokines• .• IL-10 inhibits antigen presentation and IL-12
.• TGF-beta induces overproduction of IL-10.
• VEGF (vascular endothelial growth factor),avoid immune recognition, inhibit theeffector function, prevent T cell activation,
cytokine production.
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(6) Induction of(6) Induction of
Immunosuppressive cellsImmunosuppressive cells• CD4+CD25+ T cells (constitute 5-10% of CD4+ T cells):
immunological tolerance to self-antigens, inhibition of T cellpro era on.
• Gr1+CD11b+ myeloid cells:-- Expressing the granulocyte-monocyte markers Gr1+CD11b+,accumulate in spleens, lymph nodes and blood of tumor-bearing mice.-- n ng an o y pro uc on, genera on, cefunction, lymphocytic proliferation, CD3 chain expression.
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sources forregulatory
Possible suppressive mechanisms regulatory T cells
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Possible suppressive mechanisms regulatory T cells
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7 Production of other7 Production of othersuppressive factorssuppressive factors
• IDO (Indoleamine 2, 3-dioxygenase):
and splenic DC subsets, leading to
• ganglioside (sialic acid containingy
• Prostaglandins
S i d f f hS i d f f h
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Summary: Main defences of theSummary: Main defences of the
tumors against immunitytumors against immunity
2) Dysregulated expression of adhesion / costimulatory
3) Changes in T-cell signal transduction molecules, i.e. cell death
4) Induction of immune suppressive cytokines
5) Induction of immunosuppressive cells
6) Secretion of suppressive factors
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1. Weapons from the tumors
2. Defects of immune system
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• Immune defects in T cells
• Malfunction of dendritic cell s stem
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Tumor mass
Vessel
Lymphocyte
FasL+ tumor cell
Apoptotic lymphocyte
Receptor-mediated apoptosis of lymphocytes
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– Tumor-mediated inhibition of DC generation,
– Functional impairment of DCs: lack of
– Induction of DC apoptosis by tumors
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Tumor Tumor- -derived factors with DC inhibitory propertiesderived factors with DC inhibitory properties
Tumor-derived factors Effect on DCs
VEGF tumor infiltration and generation
TGF-beta CD80 and CD86 expressionGangliosides inhibition of dendropoiesis from
hematopoietic precursor cells
-
IL-10 differentiation,CD80/CD86/CD40expression,IL-12 production
Prostanoids,prostaglandins differentiation
PgE2 generation
NO induction of apoptosis
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Summary
How do tumors progress?
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Activation versus suppression of
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pp
TumorRegression
Cytokines
Activation >suppression
T cellTumor
Suppression> activation
TumorProgression
DCNK cell
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de ends on the battle between
immune system and tumor cells
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Strategies to improve the tumor-
either boosting components of the
effective immune response or byinhibiting components that suppress
the immune response.
ImmunotherapyImmunotherapy --- --- ReverseReverse
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ImmunotherapyImmunotherapy ReverseReverse
the imbalancethe imbalance
Tumor Immunotherapy
Tumor Progression
StrategiStrategiees to supplement the missing ors to supplement the missing or
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St ategSt ateg ees to supp e e t t e ss g os to supp e e t t e ss g o
insufficient immune elementsinsufficient immune elementsImmune elements Enhancing ‘the enhancer’
T cells Injection of cytotoxic T cells
Natural killer cells Injection of activated NK cells
TAA Peptide, TAA-vector vaccination
Effector cytokines IL-2, IL-12
Strategies to block the suppreStrategies to block the suppresssive sive
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Strategies to block the suppreStrategies to block the suppresssive sive
mechanismsmechanismsSuppressive elements Inhibiting ‘the inhibitors’
Regulatory T cells Blocking their function
dysfunctional DCs Blocking the pathway
Suppressive cytokines Blocking potential commoncy o ne s gna ng
Main Mechanisms ofMain Mechanisms of
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ImmunotherapyImmunotherapy• Stimulatin the antitumor res onse either b increasin the number of effector cells or by producing solublemediators.
• Decreasing suppressor mechanisms.
• Altering tumor cells to increase their immunogenicity and.
• Im rovin tolerance to c totoxic dru s or radiotherasuch as stimulating bone marrow function with GM-CSF.
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• - o ey o serve umour regress onafter bacterial infections
• BCG vaccine to treat bladder carcinoma• 1970-80’s – c tokines
– includes interferons, interleukins and tumor
– Limited success
Current ImmunotherapeuticCurrent Immunotherapeutic
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pp
strategies in clinic or clinical trialsstrategies in clinic or clinical trials
• Antibody Therapy• Cytokine Therapy• • Vaccination• Combinational therapy
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ExamplesExamples
ntibod Therantibod Thera
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ntibod Therantibod TheraRituximab: The first approved antibody by FDA in clinical trial.Targeting CD20. low-grade non-Hodgkin lymphoma
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Local and regional IL-2 administration in cancer patients -selected examples from the early trials
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p y
Interleukin-2 Dose Tumour Response (%) Referenceun s pa en omp e e par a
gibbon lymphoid 1.5 x 10-2 – 4.0 x 10-3 urinary bladder carcinomas 30/ 30 Pizza (1984)
human recombinant 1.0 x 10-4 – 2.8 x 10-4 lung carcinomas 0/ 82 Yasumoto (1987)
human recombinant 8.0 x 10-2 – 5.4 x 10-3 malignant gliomas 13/ 13 Yoshida (1988)human lymphoid 2.0 x 10-3 squamous cell carcinomas 29/ 29 Forni (1988)human lymphoid 2.0 x 10-3 squamous cell carcinomas 30/ 30 Cortesina (1988)human lymphoid continuous perfusion urinary bladder carcinomas 20/ n.v. Huland and Huland
1.5 x 10-6/week (1989)
n.v., not verified because of incomplete transurethral resection
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• Stimulating immune cells by exposing
laboratory and then injecting expanded
patients. .
Tumor escape mechanism and T-cell adoptiveimmunotherapy after genetic manipulation
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(1) Tumor cells that produce TGFß that exert inhibitory effects on the immune system. Specific CTL can be geneticallymodified to become resistant to the TGF β inhibitory effect through transgene expression of a mutant dominant-negat ve type receptor .
(2) Specific T cells genetically modified to produce IL-12 can overcome IL-10 inhibitory effect.
(3) Tumors express FasL and induce apoptosis of effector T cells. Small interfering RNA (siRNA) can be used toknock-down Fas receptor in specific CTL, allowing a significant reduction of their susceptibility to Fas/FasL-
.
Adoptive immunotherapy Adoptive immunotherapy
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Generation of dendritic cell vaccines from eri heral blood monoc tes:1) Monocytes cultures with GM-CSF +IL-4 to produce DCs2) Matured with CD40 ligand3) Pulsed with peptide or tumour lysate
4) Re-injected as vaccine to induce T-cell immune response against tumour
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Antitumor Vaccines Antitumor Vaccines
of antigen to induce a specificof antigen to induce a specifican umour mmune response.an umour mmune response.
Antitumor Vaccines Antitumor Vaccines
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Approaches to antitumor vaccination Approaches to antitumor vaccination
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The Journal of Clinical Investigation Vol 113 ( 11) June 2004 pp 1515
APC – antigen presenting cell TAA – tumour associated antigen
DC – dendritic cell MHC – major histocompatibility complex
Dendritic Cells That Attack Cancer Dendritic cell
Complex binds matures and is
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Complex binds
to dendritic cellprecursor
matures and is
infused back intopatient
T cell
Tumor antigen
antigen islinked to acytokine
Complex istaken in bydendritic cellprecursor
Cancer cell
T cells attack cancer cell
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The immune system can be harnessed,
but only if immunotherapy is combinedwith treatment strategies that target atumour’s wea ons of survival defence
and attack. If cancer cells are prevented
generate immune escape variants.
--
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enhances the therapeutic efficacy of cancer immunotherapyenhances the therapeutic efficacy of cancer immunotherapy
, . -
Potential mechanisms for synergy displayed by combined blockinghypoxia pathway and B7.1-mediated immunotherapy
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B7.1+AS-HIFAS-HIFNK .
Tumor cell
Apoptosis Necrosis Glycolysis
ActivatesNK cells
v
cell Tumor cell
hs 70- tumor
Anti-angiogenesis
vv
APCCTumor
cellB7.1
Antigen
Heat-shock Cell vitality.
MHCIICD28
MHCI
CD28
T cell
MHCII
T cell
driven anti-tumor
immunity
Immune su ressive
Proliferation& CTL-
mediatedkilling
elements
Tumor Cell
Apoptosis
B7H3-meidated Cancer Immunotherapy
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Arsenic trioxide synergizes with B7H3-mediatedimmunotherapy to eradicate hepatocellular carcinomas
International Journal of Cancer 2006; 118:1823-1830.
omp e e era ca on o epa oce u ar carc nomas y com ne
vasostatin gene therapy and B7H3-mediated immunotherapy.-
Novel co-stimulatory molecule- B7H3
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Molecular Structure
SS IgV-like IgC-like Cytoplasmic
Signal peptideMLRGWGGPSVGVCVRTALGVLCLCLTGAVEVQVSEDPVVALVDTDATLRC
I V-like domain
Transmembrance
SFSPEPGFSLAQLNLIWQLTDTKQLVHSFTEGRDQGSAYSNRTALFPDLLVQ
GNASLRLQRVRVTDEGSYTCFVSIQDFDSAAVSLQVAAPYSKPSMTLEPNK IgC-like domain
VHSVLRVVLGANGTYSCLVRNPVLQQDAHGSVTITGQPLTFPPEALWVTVGTransmembrane Cytoplasmic
LSVCLVVLLVALAFVCWRKIKQSCEDENAGAEDQDGDGEGSKTALRPLKPS
ENKEDDGQEIA
, . .
Gene transfer results in expression of B7H3 on
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pcDNA3.1 Flag-B7H3
Flag-B7H3
Tubulin
Combinational thera led to eradication of lar e tumors
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and generation of memorized anti-tumor immunity
2
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0 1 2 3 4 5 6 7 9 12Weeks After Therapy
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Production of anti-tumor cytokine and CTLs by immunotherapy
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400 -
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• Immunotherapy may be the next great hope forcancer treatment.
• individually shown some promise, it is likely that
attack on all fronts.
traditional cancer therapies is another avenue.
Background – mini review
Controversial Not reported Shortcomings
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Unclear Further investigationIntroduction
Hypothesis
Experiments
Materials and Methods
Results
Discussion
ConclusionDiscussion Combined
Future Investi ation
gn cance
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