DC vaccine & DC vaccine & Anti-tumorAnti-tumor

““生命之树生命之树” ” 课课题组：题组：

　　　　

　　孔琰　唐跃　田亚楠　　孔琰　唐跃　田亚楠　　　王超　王京　　王超　王京　王欠欠王欠欠

The tumor induced immunity The tumor induced immunity DC vaccineDC vaccineInduce in vitro & proliferationInduce in vitro & proliferationClassification DC vaccineClassification DC vaccineThe function of DC in anti-tumorThe function of DC in anti-tumorReinfuse of DCReinfuse of DCOur opinionOur opinion

The function of DC in anti-tumorThe function of DC in anti-tumor

Mechanism of DC in anti-tumorMechanism of DC in anti-tumor

Inhibit formation of tumor vessel

NO,TNF etc

Migration proliferation

Tumor Ag DC TCTL

Tolerance

Cell apoptosis、 lysis、 CK

Influence to DC from CKs producInfluence to DC from CKs produced by tumored by tumor

VEGFCVEGFC （血管内皮生长因子）——（血管内皮生长因子）—— DepresDepress the differentiation of pre-DC to mature DCs the differentiation of pre-DC to mature DC

IL-10IL-10————Inhibit the expression of co-stimulatory Inhibit the expression of co-stimulatory molecules molecules

TGF-ßTGF-ß————Inhibit the activation of specific Inhibit the activation of specific CTLCTL

DC-SIGNDC-SIGN

DC vaccineDC vaccineDefinition:Definition: the DC derive from peripheral the DC derive from peripheral

blood mononuclear cells(blood mononuclear cells(PBMCsPBMCs) are s) are stimulated by peptide antigen,tumor lysattimulated by peptide antigen,tumor lysates,whole-cell prepration RNA or DNA of es,whole-cell prepration RNA or DNA of tumor.And the reinfuse the DC into the tumor.And the reinfuse the DC into the patient as vaccine.patient as vaccine.

HOW TO GAIN DC ?HOW TO GAIN DC ?

Peripheral blood mononuclear cells Peripheral blood mononuclear cells are proper for clinical experiment.are proper for clinical experiment.

GM-CSF / IL-4

CD14+CD14+ DCDC

CD34+ CD34+ DCDCGM-CSF / TNF-α

DC vaccine

HOW TO GAIN DC ?HOW TO GAIN DC ?

Peripheral blood mononuclear cells Peripheral blood mononuclear cells are proper for clinical experiment.are proper for clinical experiment.

GM-CSF / IL-4

CD14+ CD14+ DCDC

CD34+ CD34+ DCDCGM-CSF / TNF-α

DC vaccine

Ag pep loaded DC subcellular vaccine4

Classification DC vaccineClassification DC vaccine

Peptide-pulsed DC vaccinePeptide-pulsed DC vaccine Peptide-pulsed DC vaccinePeptide-pulsed DC vaccine1

Tumor cell lysate-sensitized DC2

DC-tumor cell hybrids3

Genetically modified DC vaccine5

11 Peptide-pulsed DC vaccinePeptide-pulsed DC vaccine

The tumor peptide in HCC is mainly alpha-fetoThe tumor peptide in HCC is mainly alpha-fetoprotein(protein(AFPAFP))

IntroductionIntroduction

AFP It has no affection to DC even at AFP It has no affection to DC even at high concention.high concention.

Glypican—3Glypican—3

HbsAg HbsAg

11 Peptide-pulsed DC vaccinePeptide-pulsed DC vaccine

AdvantagesAdvantagesTargetingTargeting, avoid unnecessary immune stimulation., avoid unnecessary immune stimulation.higher concentration of tumor Ag stimulate the higher concentration of tumor Ag stimulate the activation of T cell efficiently activation of T cell efficiently

DisadvantagesDisadvantagesThere is There is little confirmedlittle confirmed; Specific recognization; Specific recognizationLittle monoclonal tumor AgLittle monoclonal tumor Ag

2 Tumor cell lysate-sensitized DC

AdvantagesAdvantages ：： tumor cell Ag prepared by direct tumor cell Ag prepared by direct supersonic breaksupersonic break

down or repeated freezing&meltingdown or repeated freezing&melting etc. is useful etc. is useful ，，no desire for Ag recognizing epitopeno desire for Ag recognizing epitope

Disadvantages:Disadvantages: hard to supply large amount of fluid tissuehard to supply large amount of fluid tissue ；； tumor lysate include normal self-Ag,which easiltumor lysate include normal self-Ag,which easil

y induce y induce self-immune diseaseself-immune disease after immunizatio after immunizationn 。。

2 Tumor cell lysate-sensitized DC

Current SituationCurrent Situation ：： LadhamsLadhams 、、 IwashitaIwashita

AliAli

HayashiHayashi

＋DC Tumor cell

3 DC-tumor cell hybrids

DC-Tumor hybrids

＋DC Tumor cell

3 DC-tumor cell hybrids

DC-Tumor hybrids

Hybrid cell Tumor cell

Unrelated tumor cell

Tumor cell

AdvantagesAdvantages Easily abtaned from biopsyEasily abtaned from biopsy 、、 operation,HCC tisoperation,HCC tis

sue specimen fromsue specimen from ；； advanced skill to obtain padvanced skill to obtain pre-DC via cell culturere-DC via cell culture ；； hybrid cell can present hybrid cell can present HCC Ag in the form of MHC pep complexHCC Ag in the form of MHC pep complex ；； hyhybrid cells in vivo can stimulate to form lasing & brid cells in vivo can stimulate to form lasing & steady Agsteady Ag

Disadvantages:Disadvantages:Selection of hybrided cellsSelection of hybrided cells

3 DC-tumor cell hybrids

4 Antigenic peptide loaded DC subcellular vaccine

DC subcellular structure & other DC hybrids inhense

expression of DC

5 Genetically modified DC vaccine

Antigen gene (HCC HBsAg AFP)Antigen gene (HCC HBsAg AFP)

Cytokine gene(GM-CSF IL-12)Cytokine gene(GM-CSF IL-12)

Chemotactic gene (lymphotactin Lpin) Chemotactic gene (lymphotactin Lpin)

5 Genetically modified DC vaccine

AdvantagesAdvantages ：： AFP gene modefied DC vaccine can expressAFP gene modefied DC vaccine can express completely endogenously & continuously completely endogenously & continuously reduce autoimmune diseasesreduce autoimmune diseases

Disadvantages:Disadvantages:

The technology is not developedThe technology is not developed

HOT SPOTSHOT SPOTS

IL-18 & Survivin(IL-18 & Survivin( 存活素存活素 ) )

Other methods to improve the Other methods to improve the effect of DC vaccineeffect of DC vaccine

NK cell& DC cell interactionNK cell& DC cell interaction

Heat shock proteinHeat shock protein （（ HSPHSP ））Mannosalization of AgMannosalization of Ag

Other methods to improve the Other methods to improve the effect of DC vaccineeffect of DC vaccine

NK cell& DC cell interactionNK cell& DC cell interaction

Heat shock proteinHeat shock protein （（ HSPHSP ））Mannosalization of AgMannosalization of Ag

Reinfuse of DC vaccineReinfuse of DC vaccine

subcutaneous

venousLymph node ?

Ag-loaded DC

Produce selective T cell chemotactic factors

Migrate to lymph node &spleen

Self or other APC secrete IL-12

CD8+Tcell Secrete CKs & cause damage

CD4+Th0 Th1 IFN-γ TNF-α GM-CSF IL-3

FORWARDFORWARD

Until now many cancers can be treated,Until now many cancers can be treated,

such as:such as:

B cell lymphoma cancerB cell lymphoma cancer

Prostate cancerProstate cancer

Malignant melanomaMalignant melanoma

曹雪涛 (左 )正在进行大肠癌 DC疫苗研究

Development and maturation Development and maturation of DCof DC

Difference between immature DC and Difference between immature DC and mature DCmature DC

Characteristics of DCCharacteristics of DC ：： 1. the most potent APC1. the most potent APC

2.the only cell can active naïve T cell to 2.the only cell can active naïve T cell to elicit primary immune response. elicit primary immune response.

3.play an significant role in anti-tumor3.play an significant role in anti-tumor

NK cell& DC cell interactionNK cell& DC cell interaction

DC attaches at the surface of NK cell and DC attaches at the surface of NK cell and stimulates related receptors ,so these stimulates related receptors ,so these two cells can communicate in the form of two cells can communicate in the form of neural synapse.neural synapse.