Toll-Like Receptors

Toll-Like Receptors
Members of the Toll-like receptor (TLR) family recognize pathogen-associated molecular patterns (PAMPs) expressed by a wide spectrum of infectious agents. To date, over thirteen TLRs have been reported in human and mouse. TLRs activate the NF-B pathway, which regulates cytokine expression, through several adaptor molecules including MyD88, TIRAP/Mal and

Toll-Like Receptors: Bridging Innate and Adaptive Responses

TRIF. Activation of the NF-B pathway links innate and adaptive immune responses by promoting the production of inflammatory cytokines such as IL-1, IL-6, IL-8, TNF-, IL-12, and chemokines as well as inducing the expression of costimulatory molecules such as CD80, CD86, and CD40.

2010 | April
ANTIBODIES

FEATURING

Mouse TLR1
9

Human TLR4
8 7

TLR1 (h,m) TLR2 (h,m) TLR3 (h,m) TLR4 (h,m) TLR6 (h) TLR7 (h,m) TLR9 (h,m)
h=human, m=mouse

188

188

Counts

98 62 49 38 28

98 62 49 38 28

Counts
4 3 2 1 0 0 10 10
1

Left Panel: Untransfected control (left) and mouse TLR1-transfected (right) Baf/3 cell lysates were loaded at 1x105 cells/lane, and probed with 3 g/ml purified anti-TLR1 (cat. no. 14-9012) and revealed with HRP anti-rat IgG (cat. no. 18-4818). Right Panel: Peritoneal-exudate (left) and RAW264.7 (right) cell lysates were loaded at 1x105 cells/lane, probed with 3 g/ml purified anti-TLR1 (cat. no. 149012) and revealed with HRP anti-rat IgG (cat. no. 184818).

Staining of normal human peripheral blood cells with PE mouse IgG2a isotype control (cat. no. 12-4724) (yellow histogram) or PE anti-human TLR4 (cat. no. 12-9917) (grey histogram). Cells in the monocyte gate were used for analysis.

TLR4 - PE

10 TLR4-PE

10

10

Toll-Like Receptors

Toll-Like Receptor Products

Functional Grade Purified Functional Grade Biotin PerCP-eFluor 710 APC-eFluor 780 Alexa Fluor 488 Alexa Fluor 647 Alexa Fluor 700

eFluor 605NC

eFluor 650NC

eFluor 450

PerCP-Cy5.5

Polyclonal

Purified

PE-Cy5

PE-Cy7

Biotin

FITC

Mouse TLR1 TLR2

Clone eBioTR23 eBioLD5 6C2 mT2.7 T2.5

Applications FC, IP WB FC, IP, IHC/F, IHC/P FC, IHC/F, IP FC, FA, IHC, IP WB FC FC, FA FC, FA, NU, IP, IHC/F FC, FA, IP WB WB, FC ICFC, WB Applications FC, IHC WB FC, FA, IHC, IP FC, IHC/F FC, FA, IHC/F, IP, WB FC, FA, IP WB WB FC, FA, IP FC, WB WB ICFC, IP, WB

Cat. No. 9011 9012 9021 9022 9024 9032 9041 9925 9924 9926 9079 9092 9093 Cat. No. 9911 9028 9024 9029 9922 9039 9048 9920 9917 9069 9079 9099

APC

PE

TLR3 TLR4

T3.7C3 UT41 (TLR4 & TLR4/MD-2) UT12 (TLR4/MD-2, activating) MTS510 (TLR4/MD-2, blocking) UT18 (TLR4/MD-2, activating)

TLR7 TLR9 Human TLR1 TLR2

Polyclonal Polyclonal M9.D6 Clone GD2.F4 Polyclonal T2.5 TL2.3 TL2.1

TLR3 TLR4

TLR3.7 Polyclonal Polyclonal HTA125

TLR6 TLR7 TLR9

hPer6 Polyclonal eB72-1665

APPLICATION KEY: FC = Flow Cytometry; ICFC = Intracellular Staining/Flow Cytometry; IHC = Immunohistochemistry; IHC/F = IHC (Frozen); IHC/P = IHC (Paraffin); IHC/PF = IHC (Paraffin & Frozen); BA = Bioassay; FA = Functional Activity; ELISA (c) = ELISA capture; ELISA (d) = ELISA detection; ELISPOT (c) = ELISPOT capture; ELISPOT (d) = ELISPOT detection; WB = Western Blot; IP = Immunoprecipitation; NU = Neutralizing

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Q110020 Toll-Like Receptors_3_10

Toll-like Receptors
Antipodal Enhancers or Suppressors of Tumorigenesis New Targets for Cancer Therapeutics
he broad expression of Toll-like Receptors (TLRs) in tumors and increasing amounts of information indicate that TLRs play an important albeit unclaried function in cancer biology. TLR recognize and respond to exogenous and endogenous ligands through signaling pathways leading to inammatory cascade mediator production which direct the innate and adaptive immune response. it is increasingly recognized that inammatory processes play a key role in tumorigenesis. TLRs, as in other human diseases, appear to act as double edged swords in tumorigenesis (reviewed in Conroy et al, 2008 and Huang et al, 2008). Overall, research studies suggest that TLRs as a family are involved in both inhibiting and promoting cancer (Rakoff-Nahoum and Medzhitov, 2009). Parallel to the recognition of the importance of TLRs as sensors and shapers of the overall anti-tumor response, TLRs have emerged as an important application area and focus of basic research and applied to development of cancer therapeutic and vaccine research. Table 1 below illustrates specic TLR targets and Pharma activities involved in development of Cancer Therapeutics pertaining to clinical trial staging. Research focusing on TLRs in tumor biology is growing rapidly. TLRs various TLR polymorphisms have now been identied in a number of tumor types as summarized in Table 2.
Table 1. Examples of Clinical Trials of TLR Realted Targets for Cancer Therapeutics TLR Target TLR3 TLR7 TLR7 TLR9 TLR9 TLR9 TLR9 TLR9 Cancer Breast Cancer Basal Cell Carcinoma Melanoma Non-Hodgkins Lymphoma Colorectal Cancer Metastatic colorectal cancer Renal cell carcinoma NSCLC Candidate Undisclosed Imiquimod (Aldara) Imidazoquinoline (852A) 1018ISS+ Rituximab 1018ISS+ chemotherapy DSLIM HYB2055, IMO2055 (IMOxine) MAGE-A3 + Vaximmune Company Innate Pharma 3M Pharma 3M Pharma Dynavax Dynavax Mologen Idera Pharm Coley/GSK Clinical Status Preclinical Approved Phase II Phase II Phase II Phase Ib/IIa Phase II Phase III

Source: Makkouk and Abdelnoor, 2009

Table 2. TLR Expression and Polymorphisms in Tumors

TLR
TLR1

TYPE OF CANCER
Colon cancer (RNA) Lymphoma (DNA) Prostate cancer (DNA)

NOTES
Low Expression Single-nucleotide polymorphism Single-nucleotide polymorphism Slightly Increased Expression Moderate Expression Increased Expression Increased Expression Weak Expression Single-nucleotide polymorphism Increased Expression Moderate Expression Moderate Expression Increased Expression Increased Expression Moderate Expression Moderate Expression Increased Expression Increased Expression Increased Expression Increased Expression Moderate Expression Increased Expression Moderate Expression Variable Expression in benign tumors, epithelial tumors, and ovarian cancer cell lines Increased Expression

APPLICATION
RT-PCR Functional Assay Functional Assay RT-PCR, Functional Assay, IHC IHC RT-PCR IHC RT-PCR Functional Assay IHC Functional Assay RT-PCR RT-PCR RT-PCR IHC, IF RT-PCR IP, WB, Functional Assay IHC RT-PCR RT-PCR Functional Assay RT-PCR, IHC RT-PCR, WB RT-PCR, IHC

REFERENCES
Immunol 115:565574 (2005) Genes Immun 7:615624 (2006) J Natl Cancer Inst 97:525532 (2005) J Int Med Res 29:409420 (2001) Immunol 115:565574 (2005) Mol Pharmacol 66:14651477 (2004) S Biol Pharm Bull 28:886892 (2005) Eur Arch Otorhinolaryngol 264:525530 (2007) Mol Immunol 44:28502859 (2007) Genes Immun 7:615624 (2006) Cancer Immunol Immunother 58(9):1375-1385 (2009) Br J Cancer 97:598-604 (2007) JI 176:48944901 (2006) Immunol 115:565574 (2005) S Biol Pharm Bull 28:886892 (2005) Eur Arch Otorhinolaryngol 264:525530 (2007) Mol Immunol 44:28502859 (2007) Clin Cancer Res 13:45654574 (2007) Cancer Immunol Immunother 58(9):1375-1385 (2009) Mol Immunol 44:28502859 (2007) Immunol 115:565574 (2005) Clin Cancer Res 14:856-864 (2008) Cancer Immunol Immunother 58(9):1375-1385 (2009) Leuk Lymphoma 46:935-939 (2005) Cancer Immunol Immunother 58(9):1375-1385 (2009)

TLR2

Colon cancer (RNA, protein) Gastric cancer (protein) Hepatocellular carcinoma (RNA) Laryngeal carcinoma (protein) Lung cancer (RNA) Lymphoma (DNA) Ovarian tumor (protein) Pancreatic carcinoma (Incompletely resectable)

TLR3

Breast cancer (RNA) Colon cancer (RNA) Hepatocellular carcinoma (RNA) Laryngeal carcinoma (protein) Lung cancer (RNA) Melanoma (protein) Ovarian tumor (protein)

TLR4

Breast cancer (RNA) Colon cancer (RNA) Melanoma (IV stage) (protein) Ovarian tumor (protein)

TLR8

Chronic lymphocytic leukemia (RNA, protein) Ovarian tumor (protein)

TLR9

Breast cancer (RNA, protein)

RT-PCR, WB, IHC, FACS, Functional Assay IHC, Functional Assay IHC Functional Assay RT-PCR RT-PCR, IHC, Functional Assay Functional Assay RT-PCR IHC WB, IHC, Functional Assay RT-PCR RT-PCR RT-PCR Functional Assay

Mol Cancer Res 4:437447 (2006)

Cervical squamous cell carcinoma (protein) Gastric carcinoma (protein) Glioma (protein) Hepatocellular carcinoma (RNA) Lung cancer (RNA, protein) Lymphoma (DNA) Melanoma (IIIb/c or IV stage) (RNA) Ovarian tumor (protein) Prostate cancer (protein) Recurrent glioblastoma (RNA) Recurrent non-Hodgkin lymphoma (RNA) TLR10 Nasopharyngeal carcinoma (RNA) Prostate cancer (DNA)

Increased Expression Increased Expression Increased Expression Increased Expression Increased Expression Single-nucleotide polymorphism Moderate Expression Increased Expression Increased Expression Moderate Expression Moderate Expression Increased Expression Single-nucleotide polymorphism

Mol Carcinog 46:941947 (2007) Int J Med Microbiol 295:179185 (2005) Glia 54:526535 (2006) S Biol Pharm Bull 28:886892 (2005) Respir Res 6:1 (2005) Genes Immun 7:615624 (2006) J Clin Oncol 24:5716-5724 (2006) Cancer Immunol Immunother 58(9):1375-1385 (2009) Prostate 67:774781 (2007) Neuro- Oncol 8:60-66 (2006) J Immunother 29: 558-568 (2006) Cancer Epidemiol Biomarkers Prev 15:862866 (2006) J Natl Cancer Inst 97:525532 (2005)