ppt
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Tumor Escape Interaction between immune system Interaction between immune system and tumors induces changes in tumor and tumors induces changes in tumor and/or immune response resulting in and/or immune response resulting in the survival of tumor the survival of tumor Tumor changes: epigenetic Tumor changes: epigenetic 1. 1. Defect in antigen presentation: Antigen loss, Defect in antigen presentation: Antigen loss, defect in antigen presentation machinery: MHC, TAP defect in antigen presentation machinery: MHC, TAP 2. 2. Expression of FasL or lack of Fas Expression of FasL or lack of Fas 3. 3. Expression of Serpin to block granzyme B Expression of Serpin to block granzyme B 4. 4. Expression of SOCS1 inhibits IFN- Expression of SOCS1 inhibits IFN- signaling signaling 5. 5. Upregulation of HLA-E: inhibition of CTL and NK T Upregulation of HLA-E: inhibition of CTL and NK T cells by NKG2A cells by NKG2A Modulation of the immune response Modulation of the immune response 1. 1. Secretion of PGE2 or TGF- Secretion of PGE2 or TGF- : generation of T regs : generation of T regs and tolerogenic DCs and tolerogenic DCs 2. 2. Chronic inflammation derives the generation of Chronic inflammation derives the generation of
Transcript of ppt
Tumor EscapeTumor Escape Interaction between immune system Interaction between immune system
and tumors induces changes in tumor and tumors induces changes in tumor and/or immune response resulting in and/or immune response resulting in the survival of tumorthe survival of tumor
Tumor changes: epigeneticTumor changes: epigenetic1.1. Defect in antigen presentation: Antigen loss, defect in Defect in antigen presentation: Antigen loss, defect in
antigen presentation machinery: MHC, TAPantigen presentation machinery: MHC, TAP2.2. Expression of FasL or lack of FasExpression of FasL or lack of Fas3.3. Expression of Serpin to block granzyme BExpression of Serpin to block granzyme B4.4. Expression of SOCS1 inhibits IFN-Expression of SOCS1 inhibits IFN- signaling signaling5.5. Upregulation of HLA-E: inhibition of CTL and NK T cells by Upregulation of HLA-E: inhibition of CTL and NK T cells by
NKG2ANKG2A
Modulation of the immune responseModulation of the immune response1.1. Secretion of PGE2 or TGF-Secretion of PGE2 or TGF-: generation of T regs and : generation of T regs and
tolerogenic DCstolerogenic DCs2.2. Chronic inflammation derives the generation of CD11bGr1 Chronic inflammation derives the generation of CD11bGr1
MSCMSC
MHC lossMHC loss
Total loss
Haplotype loss
HLA-A or B locus-specific loss
HLA allelic loss
Antigen lossAntigen loss
HER-2
Herceptin
tumor
tumor
Loss of Fas or gain of Fas-L expression
Loss of Fas or gain of Fas-L expression
FasL
Tumor CTL
FasFasL
Tumor CTLWhen tumors loose Fas expression or gain Fas Ligand,they become refractory to Fas-L mediated lysis and kill Fas-expressing T cells
Serine Protease Inhibitors(Serpin)
Serine Protease Inhibitors(Serpin)
Antigen presenting cells and Antigen presenting cells and activated T cells express serine activated T cells express serine protease inhibitor (Serpin; spi9 in protease inhibitor (Serpin; spi9 in human and spi6 in mouse)human and spi6 in mouse)
Seprins inactivate proteases by Seprins inactivate proteases by acting as suicide substrates resulting acting as suicide substrates resulting in rescue of APCs and DCs from the in rescue of APCs and DCs from the self-destructionself-destruction
Tumors may express Serpins to Tumors may express Serpins to escape immune responsesescape immune responses
Expression of SOCS1Expression of SOCS1
Suppressor of Cytokine Signaling 1 Suppressor of Cytokine Signaling 1 (SOCS1) is induced by IL-10 and IL-6(SOCS1) is induced by IL-10 and IL-6
SOCS1 blocks IFN-SOCS1 blocks IFN- downstream downstream signaling thereby inhibiting apoptosissignaling thereby inhibiting apoptosis
Upregulation of non-classical HLA
Upregulation of non-classical HLA
-E-A
Upregulation of HLA-E expression
Upregulation of HLA-E expression
Activated T cells
T cells
IFN-
suppression
tumorHLA-ENKG2A
T cells
Generation of CD4+ CD25+ regulatory T cells (T regs)
Generation of CD4+ CD25+ regulatory T cells (T regs)
Secrete immunosuppressive molecules: prostaglandins, Secrete immunosuppressive molecules: prostaglandins, transforming growth factor beta (TGF-transforming growth factor beta (TGF-), IL-10, etc.), IL-10, etc.
Tumor T regs
CTLTGF-IL-10
Tolerogenic DCs
Imm
unos
uppr
essiv
e
Cytok
ines
(2)
CD25
Compet
e for
IL-2
(1)
Contact dependent Suppression (3)
Generation of myeloid suppressor cells (MSC):
CD11b+Gr1+
Generation of myeloid suppressor cells (MSC):
CD11b+Gr1+
TumorVEGFIL-6PGE2
Myeloid cells
Immature MSC:CD11b+Gr1+
T cell anergy
Cancer TherapyCancer Therapy
Surgery - Surgery - Localized tumorsLocalized tumors
Radiation - Radiation - Metastastic tumorsMetastastic tumors Affects proliferating cells (bone marrow, etc.) Affects proliferating cells (bone marrow, etc.) Radiation-resistant tumors developRadiation-resistant tumors develop
Chemotherapy - Chemotherapy - Metastastic tumorsMetastastic tumors Affects proliferating cells (bone marrow, etc.) Affects proliferating cells (bone marrow, etc.) Drug-resistant tumors developDrug-resistant tumors develop
Immunotherapy -Immunotherapy - Metastastic tumorsMetastastic tumors Tumor specificityTumor specificity Develop memory and is applicable in a preventive Develop memory and is applicable in a preventive
settingssettings
ImmunotherapyImmunotherapy
Active Immunization: Active Immunization: Specific: vaccinesSpecific: vaccines Non-specific: adjuvantsNon-specific: adjuvants
Passive Immunization:Passive Immunization: Specific: antibodiesSpecific: antibodies Non-specific: immunotoxinsNon-specific: immunotoxins
Adoptive ImmunotherapyAdoptive Immunotherapy
Use of MAGE, tyrosinase, gp100 as a vaccine against melanomas
Use of MAGE, tyrosinase, gp100 as a vaccine against melanomas
Expressed on normal melanocytes Expressed on normal melanocytes and melanomas – Vitiligo (skin and melanomas – Vitiligo (skin depigmentation)depigmentation)
MAGE
tumor CTL
CD28
Tumors escape the action of CTL by not expressing B7 molecule
tumor
B7
No killingNo T cell activation
KillingT cell activation
Use of B7 to induce anti-tumor immunity
CTL
TCRMHCI-Ag
NonspecificNonspecific:: BCG (Bacillus Calmette-Guerin) BCG (Bacillus Calmette-Guerin)
Mycobacteria - melanoma, bladder Mycobacteria - melanoma, bladder carcinomacarcinoma
Corynebacterium parvum (C. Corynebacterium parvum (C. parvum)parvum)
Muramyl dipeptideMuramyl dipeptide
Naive M
Tumor
Activated M
Tumor lysis
Anti-CD3 Abs - polyclonal Anti-CD3 Abs - polyclonal activation of T cellsactivation of T cells
CD3
TCR
TumorT cell
MHC
Tumor Ag
Anti-CD3T cell Activation of T cells
No activation of T cellsdue to the lack of co-stimulation
Passive ImmunizationPassive Immunization Specific:Specific: Ab Therapy Ab Therapy
Anti-idiotypic AbsAnti-idiotypic Abs
Abs against growth factor receptor e.g. IL-2R Abs against growth factor receptor e.g. IL-2R in HTLV-1 induced Adult T cell leukemiain HTLV-1 induced Adult T cell leukemia
Abs specific for oncogene product e.g. Abs Abs specific for oncogene product e.g. Abs against HER2/against HER2/neu neu (Herceptin or trastuzumab)(Herceptin or trastuzumab)
B celltumor
Idiotype
B cell
IL-2RIL-2
Anti-IL-2R Ab
Oligomerization ofHER-2/neu inducesTumor proliferation
Herceptin prevents Oligomerization ofHER-2/neu
Tumor Tumor
Anti-tumor Abs coupled to toxin, Anti-tumor Abs coupled to toxin, radioisotopes, drugs or enzymesradioisotopes, drugs or enzymes::
ImmunotoxinsImmunotoxins: :
* * Ricin A/diphtheria/Pseudomonas toxin Ricin A/diphtheria/Pseudomonas toxin coupled to Abs. e.g. antiCD22-Psudomonas coupled to Abs. e.g. antiCD22-Psudomonas toxin in hairy (B) cell leukemia toxin in hairy (B) cell leukemia
Toxin inhibits protein synthesisToxin inhibits protein synthesis
* Cytocidal isotopes or anticancer drugs * Cytocidal isotopes or anticancer drugs (adriamycin) coupled to Abs(adriamycin) coupled to Abs
TumorRicin
Inefficacy of Abs
Tumor Ag lossTumor Ag loss Shedding/internalization of tumor Ag-Ab Shedding/internalization of tumor Ag-Ab
complexescomplexes Anti-rat/mouse Ab develops causing Anti-rat/mouse Ab develops causing
anaphylaxis and serum sicknessanaphylaxis and serum sickness Half life of AbHalf life of Ab Non specific binding to FcR+ cells Non specific binding to FcR+ cells
(Mf, granulocytes, NK and B cells)(Mf, granulocytes, NK and B cells)
M
T cell Tumorcell
CD3Ag
Bispecific Ab
Human Fc
Mouse Fab
Humanized Ab
Humanized/chimeric Ab (from 2 species)Humanized/chimeric Ab (from 2 species)
Adoptive Immunotherapy
1. 1. Lymphokine-activated killer cells Lymphokine-activated killer cells (LAK): PBL + high dose IL-2(LAK): PBL + high dose IL-2
NK NK LAK LAK
2. 2. Tumor-infiltrating lymphocytes Tumor-infiltrating lymphocytes (TIL): (TIL):
In and around solid tumorsIn and around solid tumors
Activated NK and CTLActivated NK and CTL
Use of LAK cells + IL-2 to treat cancer
Use of LAK cells + IL-2 to treat cancer
Isolate lymphocytes from blood
lymphocytes
+IL-2 for 3 days
IL-2
LAKcells
melanoma
Treatment of Melanoma with LAK
cells +IL-2
Treatment of Melanoma with LAK
cells +IL-2
Before After
Use of tumor-infiltrating lymphocytes + IL-2 to
treat cancer
Use of tumor-infiltrating lymphocytes + IL-2 to
treat cancer
surgical removalof cancer nodule
tumor
T cell
+IL-2
IL-2
Treatment of melanoma and renal cell carcinoma
lymphodepletion
Treatment of Melanomas with TIL +
IL-2
Treatment of Melanomas with TIL +
IL-2
Before After
Problems associated with IL-2 therapy
Problems associated with IL-2 therapy
Induces activation-induced cell Induces activation-induced cell deathdeath
Very toxic----triggers vascular leakVery toxic----triggers vascular leak
IL-2
T cell
CD44
endothelial cells
Cytokine Therapy
1. Interleukin -2 (IL-2) high 1. Interleukin -2 (IL-2) high dose - alone dose - alone or with cellsor with cells
- activates NK and CTL - activates NK and CTL
- toxic - fever, edema, shock- toxic - fever, edema, shock
- melanoma and renal cell - melanoma and renal cell carcinomacarcinoma
2. Tumor necrosis factor (TNF-2. Tumor necrosis factor (TNF-) ) CarcinomasCarcinomas
- antiangiogenic, apoptosis- antiangiogenic, apoptosis
3.3. Interferon IFN-Interferon IFN- : : - activates NK cells and - activates NK cells and increases MHCIincreases MHCI - hairy cell leukemia, renal cell - hairy cell leukemia, renal cell carcinoma, carcinoma, melanoma, Kaposi melanoma, Kaposi sarcoma, hematologic sarcoma, hematologic cancerscancers
4.4. IFN-IFN-: : - induces apoptosis and - induces apoptosis and
increases MHCI, increases MHCI, activates activates macrophagesmacrophages
- ovarian carcinoma- ovarian carcinoma5.5. Hematopoietic growth Hematopoietic growth
factors (GM-CSF, G-CSF): factors (GM-CSF, G-CSF): - overcome neutropenia- overcome neutropenia
Gene therapyGene therapy
Introduce cytokine genes for IL-2, IL-4, IL-12,GM-CSF or IFN- into tumor cells
Tumor Ag gene expressed in DC Tumor Ag gene expressed in DC (tumor Ag usually not known).(tumor Ag usually not known).
tumorT cell
M
IL-2IL-4
GM-CSF
SUMMARYSUMMARY Interaction between immune system Interaction between immune system
and tumors induces changes in tumor and tumors induces changes in tumor and/or immune response resulting in and/or immune response resulting in the survival of tumorthe survival of tumor
Tumor changes: epigeneticTumor changes: epigenetic1.1. Defect in antigen presentation: Antigen loss, defect in Defect in antigen presentation: Antigen loss, defect in
antigen presentation machinery: MHC, TAPantigen presentation machinery: MHC, TAP2.2. Expression of FasL or lack of FasExpression of FasL or lack of Fas3.3. Expression of Serpin to block granzyme BExpression of Serpin to block granzyme B4.4. Expression of SOCS1 inhibits IFN-Expression of SOCS1 inhibits IFN- signaling signaling5.5. Upregulation of HLA-E: inhibition of CTL and NK T cells by Upregulation of HLA-E: inhibition of CTL and NK T cells by
NKG2ANKG2A
Modulation of the immune responseModulation of the immune response1.1. Secretion of PGE2 or TGF-Secretion of PGE2 or TGF-: generation of T regs and : generation of T regs and
tolerogenic DCstolerogenic DCs2.2. Chronic inflammation derives the generation of CD11bGr1 Chronic inflammation derives the generation of CD11bGr1
MSCMSC
Suggested ReadingSuggested Reading
Immunobiology: The Immune System in Immunobiology: The Immune System in Health and Disease by Janeway et al. 6Health and Disease by Janeway et al. 6 thth edition, 2005. Pg. 630-642edition, 2005. Pg. 630-642
