Anticancer immunity 2013

Anti-Cancer Immunity

Jesse Liang, Ph.D.

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Sample & Assay Technologies

Cancer from an Immune Perspective

Cancers are not infectious agents and therefore lack the
molecular signatures that normally enable the immune
system to recognize and react. This appears to be the root
of the problem.
This is not to say that tumors are invisible to the immune
system. Tumors are frequently heavily infiltrated by
macrophages and neutrophils. But such cells are often
actively recruited by the tumor and can promote tumor
proliferation, angiogenesis, and progression through the
production of inflammatory mediators and reactive oxygen
or nitrogen species that provoke DNA damage and thus
additional mutations.
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Cancer Immunoediting

Strongly immunogenic tumors would fail to develop to the
point that they become clinically significant. In this way, the
immune system may exert a selective pressure for cancercausing mutations (such as ras point mutation, complete loss
of p53 or Rb) that are largely immunologically silent – a
process that is termed immunoediting.
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In other words, immunoediting is a process ranging from
immune surveillance to immune escape. It’s an immune
selection.
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Cancer Immunoediting – 3E Theory

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Phase 1: Recognition, infiltrating, recruiting
Phase 2: Induce tumor death

Elimination
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Phase 3: Promote more tumor death
Phase 4: Destroy all tumor cells

Equilibrium: Tumor cells which have survived the elimination phase enter
the equilibrium phase.

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Escape: Tumor cells which have acquired resistance to equilibrium enter
the escape phase.

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Cancer Immunoediting

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Tumor Escape Mechanisms – Immunosuppression

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Tumor-Derived Soluble Factors

Tumor cells produce immunosuppressive factors:

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IL-10, TGF-β, VEGF, Prostaglandins, etc.

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Cellular Components:

Regulatory T cells (Tregs), Myeloid-derived suppressor cells (MDSCs) and
invariant Natural Killer T cells (iNKTs).

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How do Cancer Cells Become Resistant to Elimination?

Paper 1:
We demonstrate that the strong immunogenicity of an
unedited tumor can be ascribed to expression of highly
antigenic mutant proteins. Outgrowth of tumor cells that lack
these strong antigens through a T-cell-dependent
immunoselection process represents one mechanism of
cancer immunoediting (Nature, Feb 2012).

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How do Cancer Cells Become Resistant to Elimination?

Paper 2:
By comparing the development of tumors in immunecompetent mice to that in mice with broad immunodeficiency
or specific antigenic tolerance, we show that recognition of
tumor-specific-antigens by lymphocytes is critical for
immunoediting. Furthermore, primary sarcomas were edited to
become less immunogenic through the selective outgrowth of
cells that were able to escape T cell attack. Loss of tumor
antigen expression or presentation on MHC (Major
Histocompatibility Complex) class I was necessary and
sufficient for this immunoediting process to occur. These
results highlight the importance of tumor-specific-antigen
expression in immune surveillance, and potentially,
immunotherapy (Nature, Feb 2012).

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Conclusion

T cell recognition of tumor antigens is key to cancer immunoediting.

The Clinical Case of Cancer Immunoediting:
Most glioblastoma at relapse are negative for EGFRvIII expression,
a relevant and direct example of cancer immunoediting (Expert Rev
Anticancer Ther, Nov 2011).
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The Induction of Anti-Cancer Immunity

1. Tumor cells express tumor-associated antigens on MHC
class I.

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2. Cytotoxic T cells recognize tumor-associated antigens and
kill tumor cells.
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3. Dendritic cells (DCs), which are important antigen
presenting cells (APCs), take up and process antigen from
dead or dying tumor cells, present the tumor-associated
antigens on MHC class I and II and stimulate T cells and other
immune cells.
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Anti-Cancer Immunotherapies

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1. Nonspecific immune stimulation:

* Stimulate T cells

IL-2

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IFNα

* Activate dendritic cells

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TLR7 agonist imiquimod

anti-CD25 antibody

* Inhibit / deplete Treg cells

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low dose cyclophosphamide

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2. Immune Checkpoint Blockade

Block CTLA4-B7 and PD1-PDL1 interactions –
The CTLA4-blocking antibody ipilimumab (Bristol-Myers Squibb)
has been approved by FDA for treating melanoma in March 2011.
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3. Adoptive Cell Transfer

Two main approaches are being explored:

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* T cells that reside in the tumor are cultured and expanded ex vivo in
the presence of IL-2. When enough of these polyclonal T cells are
obtained, they are re-infused into the patient.

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* Isolated peripheral blood T cells are transfected to express tumorantigen-specific TCRs (T Cell Receptors) and then re-administered to
the patient. This strategy has the advantage that enough T cells can
be obtained for infusion in all patients, but a potential drawback is
that the TCRs that are transfected into the T cells have a limited
antigen-specificity repertoire.

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4. Cellular Vaccines

* Tumor cell or tumor antigen vaccination
Extracted, irradiated tumor cells are re-administered to the patient. Adjuvants
such as TLR agonists or GM-CSF are required.
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* APC vaccination
APCs are extracted from a patient’s bloodstream, cultured and activated with
cytokines or adjuvants, loaded with tumor antigen ex vivo, and re-administered to
the patient. Sipuleucel-T (made by Dendreon) has been approved by FDA for
prostate cancer treatment in April 2010.
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* DC vaccination
DCs are cultured from peripheral blood monocytes in the presence of IL-4 and
GM-CSF, and activated and loaded with tumor antigen ex vivo, and readministered to the patient.
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Inflammasomes and Anti-Cancer Immunity
Inflammasomes in carcinogenesis and anticancer immune responses

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Nature Immunology 13, 343-351, 2012 (March 18, 2012)

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The inhibition of inflammasomes or neutralization of their products, mainly interleukin 1β (IL1β) and IL-18, has profound effects on carcinogenesis and tumor progression.

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Inflammasomes PCR Arrays

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http://www.sabiosciences.com/rt_pcr_product/HTML/PAHS-097Z.html

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Profiling Gene Expressions –

Using RT2 Profiler PCR Array

84 Pathway-Specific
Genes of Interest
5 Housekeeping Genes
Genomic DNA
Contamination Control
Reverse Transcription
Controls (RTC) n=3
Positive PCR Controls
(PPC) n=3


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PCR Array Work Flow
cDNA Synthesis (kit)
45 minutes
Load Plates (Use 8-Channel
Pipettors)
2 minutes

Run 40 cycle qPCR Program
2 to 2.5 hours
compatible with all major
real-time PCR instruments

Upload and Analyze Data
15 minutes

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T Cell and B Cell Activation PCR Array

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T-Cell Activation:
Regulators of T-Cell Activation: CD2, CD276, CD47, DPP4, CD3D, CD3E, CD3G, CD4, CD7, CD80, CD86,
CD8A, CD8B, FOXP3, ICOSLG, IRF4, LAG3, LCK, MAP3K7 (TAK1), MICB, NCK1, TNFSF14, VAV1.
T-Cell Proliferation: CD28, CD3E, ICOSLG, IL1B, IL10, IL12B, IL18, NCK1, RIPK2, TNFSF14.
T-Cell Differentiation: ADA, APC, BCL2, BLM, CD1D, CD2, CD27 (TNFRSF7), CD4, CD80, CD86, EGR1,
IL12B, IL15, IL2, IRF4, NOS2 (iNOS), PTPRC, SOCS1.
T-Cell Polarization: CCL3, CCR1, CCR2, CCR3, CCR4, CCR5, CD274, CD28, CD4, CD40LG (TNFSF5),
CSF2 (GM-CSF), CXCR3, CXCR4, IFNG, IL12A, IL12RB1, IL12RB2, IL18R1, IL2, IL4, IL4R, IL5, TGFB1.
Regulators of Th1 and Th2 Development: CD2, CD40 (TNFRSF5), CD5, CD7, CSF2 (GM-CSF), IFNG,
IL10, IL12A, IL13, IL3, IL4, IL5, TLR2, TLR4, TLR9.
Th1 & Th2 Differentiation: CD28, CD40 (TNFRSF5), CD40LG (TNFSF5), CD86, IFNG, IL12A, IL12B,
IL12RB1, IL12RB2, IL18, IL18R1, IL2, IL2RA, IL4, IL4R, IL6.
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B-Cell Activation:
Antigen Dependent B-cell Activation: CD28, CD4, CD40 (TNFRSF5), CD40LG (TNFSF5), CD80, FAS
(TNFRSF6), FASLG (TNFSF6), IL10, IL2, IL4.
Other Genes involved in B-Cell Activation: ADA, CXCR5, ICOSLG, IL6, IL7, MS4A1, TGFB1.
B-Cell Proliferation: BCL2, CD27 (TNFRSF7), CD40 (TNFRSF5), CD81, IL10, IL7, PTPRC.
B-Cell Differentiation: ADA, AICDA, BLNK, CD27 (TNFRSF7), IL10, IL11, IL4, RAG1.
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Other Immune Cell Activation:
Macrophage Activation: IL13, IL4, TLR1, TLR4, TLR6.
Neutrophil Activation: IL8.
Natural Killer Cell Activation: CD2, IL12A, IL12B, IL2.
Leukocyte Activation: CX3CL1.
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Th1-Th2 Responses PCR Array
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Th1 Genes:
Th1 Markers: CCR5, CXCR3, IFNG, STAT4, TBX21.
Th1 Immune Response: CCR2, CD80, EBI3, IL12B, IL18, IL1RL1 (ST2), IL27, IL27RA, IL4R (CD124), SLC11A1, SOCS5,
TLR4, TLR6, TNFSF4, VEGFA.
Other Th1-Related Genes: CD28, CD40LG (TNFSF5), CSF2 (GM-CSF), HAVCR2, IL12RB2, IL18R1, IL2, IL2RA, IRF1,
SOCS1, STAT1, TNF.
Cell-Mediated Immunity:
BCL6, CD27 (TNFRSF7), CD28, CD40LG (TNFSF5), IFNG, IL10, IL12B , IL2, IL27RA, IL4, IL7R, LTA (TNFB), PTPRC,
SLC11A1, STAT6, TBX21, TLR4, TNF, TNFSF4.
Th2 Genes:
Th2 Markers: CCR4, GATA3, IL13, IL25 (IL17E), IL2RA (CD25), IL4, IL4R (CD124), IL5, STAT6.
Th2 Immune Response: BCL6, CCR2, CD86, IL10, IL18, IL27RA, IL6, SOCS5, TNFSF4.
Other Th2-Related Genes: CCL11 (Eotaxin), CCL5 (RANTES), CCL7 (MCP-3), CCR3, CEBPB, GFI1, GPR44, ICOS,
IL13RA1, IL1R1, IL9, IRF4, JAK1, MAF, NFATC1, NFATC2, PCGF2 (RNF110).
Humoral Immunity:
CD28, EBI3, IFNG, IL6, IL7, LTA (TNFB), TNF.
CD4+ T Cell Markers:
CD27 (TNFRSF7), CD4, CD40LG (TNFSF5), CD80, CD86, CREBBP, CTLA4, FASLG (TNFSF6), IL15, IL6, IL6R, IL7, JAK2,
LAG3, LAT, MAPK8 (JNK1), PTPRC, TGFB3, TNFRSF8, TNFRSF9, TNFSF4 (OX40L), TYK2, YY1.
Other Genes Involved in Inflammatory Response: JAK2, LTA (TNFB), SPP1 (Osteopontin).
Other Genes Involved in Immune Response: IL3, SFTPD.
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----------------------------------------------------------------------------------------------------------------------------------------------Nakata Y, Brignier AC, Jin S, Shen Y, Rudnick SI, Sugita M, Gewirtz AM.
c-Myb, Menin, GATA-3, and MLL form a dynamic transcription complex that plays a pivotal role in human T
helper type 2 cell development. Blood. 2010 Aug 26;116(8):1280-90.
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Th17 PCR Array

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Surface Molecules: CD28, CD34, CD4, CD8A, ICAM1, ICOS, TLR4.

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Chemokines: CCL1 (I-309), CCL2 (MCP-1), CCL20 (MIP-3A), CCL22 (MDC), CCL7 (MCP-3), CX3CL1,
CXCL1, CXCL12 (SDF1), CXCL2, CXCL5 (ENA78/LIX), CXCL6 (GCP-2), IL8, MMP3, MMP9.

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Cytokines: CSF2 (GM-CSF), CSF3 (GCSF), IFNG, IL10, IL12B, IL13, IL15, IL17A, IL17C, IL17D, IL17F,
IL18, IL1B, IL2, IL21, IL22, IL23A, IL25 (IL17E), IL27, IL3, IL4, IL5, IL6, IL9, TGFB1, TNF.

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Cytokine Receptors: CCR2, CCR4, CCR6, IL1R1, IL12RB1, IL12RB2, IL17RA, IL17RB, IL17RC, IL17RE,
IL23R, IL6R, IL7R.

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Signaling Pathway Molecules and Transcriptional Factors: CD40LG (TNFSF5), CEBPB, CLEC7A
(Dectin-1), FOXP3, GATA3, IRF4, ISG20, JAK1, JAK2, NFATC2, NFKB1, RORA, RORC, RUNX1 (AML1),
S1PR1, SOCS1, SOCS3, STAT3, STAT4, STAT5A, STAT6, SYK, TBX21, TRAF6.
--------------------------------------------------------------------------------------------------------------------------------------------Kobayashi T, Matsuoka K, Sheikh SZ, Elloumi HZ, Kamada N, Hisamatsu T, Hansen JJ, Doty KR, Pope
SD, Smale ST, Hibi T, Rothman PB, Kashiwada M, Plevy SE .
NFIL3 is a regulator of IL-12 p40 in macrophages and mucosal immunity. J Immunol. 2011 Apr
15;186(8):4649-55.

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Cytokines and Chemokines PCR Arrays

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Chemokines: CCL1, CCL11, CCL13, CCL17, CCL18, CCL19, CCL2, CCL20, CCL21, CCL22, CCL24,
CCL3, CCL5, CCL7, CCL8, CX3CL1, CXCL1, CXCL10, CXCL11, CXCL12, CXCL13, CXCL16, CXCL2,
CXCL5, CXCL9, PF4, PPBP, XCL1.

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Interleukins: IL10, IL11, IL12A, IL12B, IL13, IL15, IL16, IL17A, IL17F, IL18, IL1A, IL1B, IL1RN, IL2, IL21,
IL22, IL23A, IL24, IL27, IL3, IL4, IL5, IL6, IL7, IL8, IL9.
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Interferons: IFNA2, IFNG.

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Growth Factors: BMP2, BMP4, BMP6, BMP7, CNTF, CSF1, CSF2, CSF3, GPI, LIF, MSTN, NODAL,
OSM, THPO, VEGFA.
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TNF Superfamily: CD40LG, FASLG, LTA, LTB, TNF, TNFRSF11B, TNFSF10, TNFSF11, TNFSF13B.

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Other Cytokines: ADIPOQ, MIF, SPP1, TGFB2.

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Anti-Inflammatory Cytokines: CCL18, CCL19, CCL21, IL10, IL11, IL12A, IL12B, IL13, IL18, IL2, IL22,
IL23A, IL24, IL4, IL6, TGFB2.

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T Helper Cell Differentiation PCR Arrays

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Cytokines & Receptors:
CCL5 (RANTES), CCL7 (MCP-3), CCR3, CCR4, CCR5, CCR6, IL12B, IL12RB2, IL13, IL13RA1, IL17A,
IL17RE, IL18, IL18R1, IL18RAP, IL1R1, IL1R2, IL1RL1, IL2, IL21, IL2RA, IL4, IL4R, IL5, IL9, TNF.
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T Helper 1 Subtype Markers:
CCR5, HAVCR2, IGSF6, IL12B, IL18, IRF1, SOCS1, SOCS5, TLR4, TLR6, TNF.

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T Helper 2 Subtype Markers:
CCL5 (RANTES), CCL7 (MCP-3), CCR3, CCR4, CEBPB, GFI1, GPR44, ICOS, IL13RA1, IL4R, JAK1,
NFATC1, NFATC2.

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Transcription Factors:
CEBPB, FOSL (FRA-1)1, FOXP3, GATA3, GATA4, HOXA10, HOXA3, ID2, IRF4, IRF8, MAF, NFATC1,
NFATC2, NR4A1, NR4A3, POU2F2, REL, RELB, RORA, RORC, RUNX1 (AML1), RUNX3, STAT1,
STAT4, STAT6, TOX, ZBTB7B.
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Epigenetically Regulated Genes:
Th1 Cells: EOMES, IFNG, IL12RB2, IL18R1, IL18RAP, FASLG (TNFSF6), TBX21.
Th2 Cells: ASB2, GATA3, IL13, IL1RL1, IL4, IL5, PPARG.
Th17 Cells: IL17A, IL17RE, IL1R1, IL21, RORA, RORC.
Inducible and Natural Regulatory T (iTreg and nTreg) Cells: CCR6, FOSL1 (FRA-1), FOXP3, IKZF2, IL9,
IRF4, IRF8, MYB, NR4A1, NR4A3, POU2F2, REL, RELB, TGIF1, TNFSF11.
Conventional Versus Regulatory T Cells: CACNA1F, CHD7, FOXP3, GATA4, HOPX, HOXA10, HOXA3,
ID2, IKZF2, IL1R2, IL2RA, KIF2C, LRRC32, PERP, PKD2, TNFRSF9, TP53INP1, UTS2.
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T Cell Anergy & Immune Tolerance PCR Array

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T-Cell Regulators:
BTLA, CBLB, CD27, CD28, FAS, FOXP3, IL15, IL2, IL2RA, IL4, LAT, TGFB1, TNFRSF14, TNFSF14.
B-Cell Regulators:
BTLA, CD27, CD40, CD40LG, FOXP1, FOXP3, HDAC9, IL4.
Cytokines, Cytokine Receptors and their related Proteins:
CCL3L1, CCR4, CD40LG, CD70, CSF1, CSF2, FASLG, IFNG, IL10, IL10RA, IL13, IL15, IL17A, IL1A, IL2,
IL2RA, IL2RB, IL31, IL4, IL5, IL6, IL7R, LEP, LTA, PRF1, PTGER2, PTGS2, TGFB1, TNFSF10, TNFSF14,
TNFSF8.
TNF Superfamily Members and their Receptors:
CD40LG, CD70, FAS, FASLG, LTA, TNFRSF10A, TNFRSF4, TNFRSF18, TNFRSF4, TNFRSF8,
TNFRSF9, TNFSF10, TNFSF14, TNFSF8.
Transcriptional Regulators:
CDK2, CDK4, EGR2, EGR3, EOMES, FOS, FOXP1, FOXP2, FOXP3, GATA3, HDAC9, IFNG, ING4, IRF4,
JAK3, JUN, MEF2A, NFATC1, NFATC2, NFATC3, NFKB1, NHLH2, NOTCH1, STAT3, STAT6, TBX21,
TGFB1.
Other Genes involved in T-cell Anergy:
CMA1, CTLA4, DGKA, DGKZ, GZMB, ICAM1, ICOS, ITCH, ITGA1, JAK1, LGALS3, PDCD1, PRKCG,
RNF128, SELL.
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Gorczynski RM, Chen Z, He W, Khatri I, Sun Y, Yu K, Boudakov I
Expression of a CD200 transgene is necessary for induction but not maintenance of
tolerance to cardiac and skin allografts. J Immunol. 2009 Aug 1;183(3):1560-8.
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Dendritic & Antigen Presenting Cells (APCs) PCR Array
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Antigen Uptake:
CD44, CDC42, ICAM1, ICAM2, RAC1, TAP2 (ABCB3).
Antigen Presentation:
CCL19, CD1A, CD1B, CD1C, CD1D, CD209, CD28, CD4, CD40 (TNFRSF5), CD40LG (TNFSF5),
CD74, CD80, CD86, CD8A, HLA-A, HLA-DMA, HLA-DPA1, TAPBP, THBS1.
Dendritic Cell Chemotaxis:
CCL19, CCL5 (RANTES), CCR1, CCR2, CCR5, CXCR1 (IL8RA), CXCR4.
Dendritic Cell Differentiation:
CSF2 (GM-CSF), LYN, RELB, TGFB1.
Cytokines:
CCL11 (Eotaxin), CCL13 (MCP-4), CCL16 (HCC4), CCL19, CCL2 (MCP-1), CCL3 (MIP-1A), CCL5
(RANTES), CCL7 (MCP-3), CCL8 (MCP-2), CSF2 (GM-CSF), CXCL1, CXCL10 (INP10), CXCL12
(SDF1), CXCL2, FLT3LG, IFNG, IL10, IL12A, IL12B, IL16, IL2, IL6, IL8, MIF, TNF, TNFSF11.
Cytokine Receptors:
CCR1, CCR2, CCR3, CCR5, CSF1R, CXCR1 (IL8RA), CXCR4, FLT3, ERBB2 (HER2).
Other Cell Surface Receptors:
CD2, CD40 (TNFRSF5), FCER1A, FCER2, FCGR1A, LRP1, TLR1, TLR2, TLR7, TLR9, VCAM1.
Signal Transduction:
CDKN1A (p21CIP1/WAF1), CEBPA, CLEC4C, FAS (TNFRSF6), IRF7, IRF8, ITGAM, ITGB2, LYN,
NFKB1, PTPRC, RELA, RELB, STAT3, TGFB1.

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Innate & Adaptive Immune Response PCR Array

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Innate Immunity:
Pattern Recognition Receptors: DDX58 (RIG-I), NLRP3, NOD1 (CARD4), NOD2, TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9.
Cytokines: CCL2 (MCP-1), CCL5 (RANTES), CSF2 (GM-CSF), CXCL10, IFNA1, IFNB1, IL18, IL1A, IL1B, IL2, IL8, TNF.
Other Genes: APCS, C3, CASP1 (ICE), CD14, CD4, CD40 (TNFRSF5), CD40LG (TNFSF5), CD8A, CRP, HLA-A, HLA-E, IL1R1, IRAK1, IRF3, IRF7,
ITGAM, LY96 (MD-2), LYZ, MAPK1 (ERK2), MAPK8 (JNK1), MBL2, MPO, MX1, MYD88, NFKB1, NFKBIA (IkBa/Mad3), STAT1, TICAM1 (TRIF),
TRAF6.
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Adaptive Immunity:
Th1 Markers/Immune Response: CCR5, CD80, CXCR3, IFNG, IL18, IL23A, SLC11A1, STAT4, TBX21, TLR4, TLR6.
Th2 Markers/Immune Response: CCR4, CCR8, CD86, GATA3, IFNB1, IL10, IL13, IL18, IL4, IL5, IL6, NOD2, STAT6.
Th17 Markers: CCR6, IL17A, RORC, STAT3.
Treg Markers: CCR4, CCR8, FOXP3, IL10.
T Cell Activation: CD80, CD86, ICAM1, IFNG, IL23A, IL6, SLC11A1.
Cytokines: CCL2 (MCP-1), CCL5 (RANTES), CSF2 (GM-CSF), CXCL10 (INP10), IFNA1, IFNG, IL10, IL13, IL17A, IL18, IL2, IL23A, IL4, IL5, IL6, IL8,
TNF.
Other Genes: CD4, CD40 (TNFRSF5), CD40LG (TNFSF5), CD8A, CRP, FASLG (TNFSF6), HLA-A, IFNAR1, IFNGR1, IL1B, IL1R1, IRF3, IRF7,
ITGAM, JAK2, MAPK8 (JNK1), MBL2, MX1, NFKB1, RAG1, STAT1.
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Humoral Immunity: C3, CCL2 (MCP-1), CCR6, CRP, IFNB1, IFNG, IL6, MBL2, NOD2, TNF.
Inflammatory Response: APCS, C3, CCL5 (RANTES), CRP, FOXP3, IL1A, IL1B, IL4, IL6, MBL2, STAT3, TNF.

Defense Response to Bacteria: IFNB1, IFNG, IL23A, IL6, LYZ, MBL2, MYD88, NOD1 (CARD4), NOD2, SLC11A1, TLR1, TLR3, TLR4, TLR6, TLR9,
TNF.
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Defense Response to Viruses: CD4, CD40 (TNFRSF5), CD86, CD8A, CXCL10 (INP10), DDX58 (RIG-I), HLA-A, IFNAR1, IFNB1, IL23A, IL6, IRF3,
NLRP3, TICAM1 (TRIF), TLR3, TLR7, TLR8, TYK2.

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McMahon L, Schwartz K, Yilmaz O, Brown E, Ryan LK, Diamond G.
Vitamin D-mediated induction of innate immunity in gingival epithelial cells. Infect Immun. 2011 Jun;79(6):2250-6.

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Toll-Like Receptors (TLRs) PCR Array
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Toll-Like Receptors:
CD180 (LY64), SIGIRR, TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10.
Pathogen-Specific Responses:
Bacterial: CCL2 (MCP-1), CD14, CD180 (LY64), FOS, HRAS, IL10, IL12A, IL1B, IL6, IL8, IRAK1, HMGB1, HSPA1A (HSP70 1A), JUN, LTA (TNFB),
LY86 (MD-1), LY96, NFKBIA (IKBA/MAD3), PTGS2 (COX2), RELA, RIPK2, TLR2, TLR4, TLR6, TNFRSF1A, TICAM1 (TRIF).
Viral: EIF2AK2 (PRKR), IFNB1, IFNG, IL12A, IL6, IRF3, PRKRA, RELA, TBK1, TLR3, TLR7, TLR8, TNF, TICAM1 (TRIF).
Fungal/Parasitic: CLEC4E, HRAS, HSPA1A (HSP70 1A), IL8, TLR2, TIRAP.
TLR Signaling:
Negative Regulation:SARM1, SIGIRR, TOLLIP.
TICAM1 (TRIF)-Dependent (MYD88-Independent): IRF3, MAP3K7 (TAK1), TAB1, NR2C2, PELI1, TBK1, TICAM2, TLR3, TLR4, TRAF6, TICAM1
(TRIF).
MYD88-Dependent: IRAK1, IRAK2, MAP3K7 (TAK1), TAB1, MYD88, NR2C2, TIRAP, TLR1, TLR10, TLR2, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9,
TRAF6.
Downstream Pathways and Target Genes:
NFkB Pathway:BTK, CASP8, CHUK (IKKa), ECSIT (SITPEC), FADD, IKBKB, IL10, IL1B, IRAK1, IRAK2, IRF3, LY96, MAP3K1 (MEKK), MAP3K7,
MAP4K4, NFKB1, NFKB2, NFKBIA (IKBA/MAD3), NFKBIL1, NFRKB, PPARA, REL, RELA, TNF, TNFRSF1A, UBE2N.
JNK/p38 Pathway:ELK1, FOS, IL1B, JUN, MAP2K3 (MEK3), MAP2K4 (JNKK1), MAP3K1 (MEKK), MAP3K7, MAPK8 (JNK1), MAPK8IP3, TNF.
JAK/STAT Pathway: CCL2 (MCP-1), CSF2 (GM-CSF), IFNG, IL12A, IL2, IL6.
Interferon Regulatory Factor (IRF) Pathway:CXCL10 (INP10), IFNA1, IFNB1, IFNG, IRF1, IRF3, TBK1.
Cytokine-Mediated Signaling Pathway: CCL2 (MCP-1), CSF3 (GCSF), IL1A, IL1B, IL6, IRAK1, IRAK2, RELA, SIGIRR, TNF, TNFRSF1A.
Regulation of Adaptive Immunity:CD80, CD86, HSPD1, IFNG, IL10, IL12A, IL1B, IL2, MAP3K7, TRAF6.
Adaptors & TLR Interacting Proteins:BTK, CD14, HMGB1, HRAS, HSPA1A (HSP70 1A), HSPD1, LY86 (MD-1), LY96 (MD-2), MAPK8IP3, MYD88,
PELI1, RIPK2, SARM1, TICAM1 (TRIF), TICAM2 (TRAM), TIRAP, TOLLIP.
Effectors:CASP8 (FLICE), EIF2AK2 (PRKR), FADD, IRAK1, IRAK2, IRAK4, MAP3K7 (TAK1), TAB1, NR2C2, PPARA, PRKRA, ECSIT (SITPEC),
TRAF6, UBE2N.
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Schluter A, Espinosa L, Fourcade S, Galino J, Lopez E, Ilieva E, Morato L, Asheuer M, Cook T, McLaren
A, Reid J, Kelly F, Bates S, Aubourg P, Galea E, Pujol .
Functional genomic analysis unravels a metabolic-inflammatory interplay in adrenoleukodystrophy. Hum
Mol Genet. 2012 Mar 1;21(5):1062-77.
Chiesa S, Morbelli S, Morando S, Massollo M, Marini C, Bertoni A, Frassoni F, Bartolome ST, Sambuceti
G, Traggiai E, Uccelli A
A Mesenchymal stem cells impair in vivo T-cell priming by dendritic cells. Proc Natl Acad Sci U S A. 2011
Oct 18;108(42):17384-9.
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Next Generation Sequencing (NGS)
Why spend time sequencing the entire genome when your research
is focused on a few genes?
QIAGEN now offers GeneRead DNAseq Gene Panels, with which you can
analyze genetic variants among specific genes of your interest or pre-selected,
cancer-focused gene panels. These panels, each with a small number of
thoroughly researched genes, enable:
• Deep sequencing
• Identification of low-frequency genetic variants
• Savings in time, money and sample usage
GeneRead DNAseq Gene Panels use multiplex PCR target enrichment
technology based on sophisticated primer design and pooling algorithms.
The PCR primer sets cover the protein-coding regions and untranslated regions
(UTRs) of all human genes. Each panel includes integrated controls to identify
poor-quality samples / libraries before sequencing.
http://www.sabiosciences.com/NGS.php
- 27 -


Next Generation Sequencing (NGS)

• Comprehensive Cancer
• Breast Cancer
• Colon Cancer
• Prostate Cancer
• Lung Cancer
• Liver Cancer
• Ovarian Cancer
• Gastric Cancer
• Leukemia

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Next Generation Sequencing - Breast Cancer Gene Panel
AKT1
CDH1
FBXW7
KRAS
APC
CDKN2A
FGFR1
NRAS
BRAF
CTNNB1
FGFR2
PIK3CA
BRCA1
EGFR
HRAS
PTEN
BRCA2
ERBB2
KIT
TP53
- 29 -


We Provide Service – Send Samples to Us & Receive Results!
Whole Genome
Illumina Gene Expression Profiling
Illumina Genotyping

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Pathway / Focused Panel
Mutation Profiling
Methylation
PCR Array
miRNA PCR Array

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Individual Gene / Locus
Mutation Detection
Methylation
qPCR

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Sample Preparation – DNA, RNA Extraction and Purification
Cells, Tissue or Biofluids
Fixed Tissue
Small Sample

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http://www.sabiosciences.com/servicecore.php

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Contact Information

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Jesse Liang
Email: jesse.liang@qiagen.com
Technical Support: 1-888-503-3187
Email: support@sabiosciences.com
Check Webinar Calendar:

http://www.sabiosciences.com/seminarlist.php
Next Generation Sequencing (NGS): December 18 (Tuesday)
Mutation PCR Arrays: December 20 (Thursday)

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