TLR3 signaling in a hepatoma cell line is skewed towards apoptosis

In addition to promoting tumor progression and metastasis by enhancing angiogenesis and invasion, myeloidderived suppressor cells (MDSC) and tumor-associated macrophage (TAM) also inhibit antitumor T-cell functions and limit the efficacy of immunotherapeutic interventions. Despite the importance of these leukocyte populations, a simple method for their specific depletion has not been developed. In this study, we generated an RNA aptamer that blocks the murine or human IL-4 receptor-a (IL4Ra or CD124) that is critical for MDSC suppression function. In tumor-bearing mice, this anti-IL4Ra aptamer preferentially targeted MDSCs and TAM and unexpectedly promoted their elimination, an effect that was associated with an increased number of tumorinfiltrating T cells and a reduction in tumor growth. Mechanistic investigations of aptamer-triggered apoptosis in MDSCs confirmed the importance of IL4Ra-STAT6 pathway activation in MDSC survival. Our findings define a straightforward strategy to deplete MDSCs and TAMs in vivo, and they strengthen the concept that IL4Ra signaling is pivotal for MDSC survival. More broadly, these findings suggest therapeutic strategies based on IL4Ra signaling blockades to arrest an important cellular mechanism of tumoral immune escape mediated by MDSCs and TAM in cancer. Cancer Res; 72(6); 1373-83. Ó2012 AACR.

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“…[24][25][26][27][28] or activation of RNA-dependent protein kinase (PKR; refs. [29][30][31][32][33].…”

Section: Il4ra Mediates a Prosurvival Signaling In Mdscsmentioning

confidence: 99%

Aptamer-Mediated Blockade of IL4Rα Triggers Apoptosis of MDSCs and Limits Tumor Progression

et al. 2012

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“…It is an interesting paradox that TLRs are expressed in invasive cancerous cells. TLR3 is expressed in breast cancer (10), melanoma (11), prostate cancer (12), cervical cancer (13), colon cancer (13), hepatocellular carcinoma (14) and head and neck cancer (15), while TLR4 is expressed in lung cancer (17). In HNSCCs, studies of TLR expression have been reported by only two investigators (15,16).…”

Section: Discussionmentioning

confidence: 99%

“…These unique pathways also induce T-cell activation and differentiation, which result in immune responses against tumor cells. On the other hand, an investigator has recently reported that stimulation of TLR3 could directly cause tumor cell apoptosis (10)(11)(12)(13)(14). In breast cancer (10), melanoma (11), prostate cancer (12), cervical cancer (13), colon cancer (13) and hepatocellular carcinoma (14), TLR3 directly induced cell apoptosis with poly I:C. However, only one study was reported in HNSCCs.…”

Section: Discussionmentioning

confidence: 99%

“…Of the TLRs, TLR3-signaling directly induces apoptosis in a variety of cancer cell lines, including breast cancer, hepatocellular cancer, cervical cancer, colon cancer and melanoma (10)(11)(12)(13)(14). The expression of TLRs and the association of gene polymorphisms of TLR in HNSCC have also been reported (15,16); however, TLR signaling by ligand stimulation in HNSCCs has not yet been closely investigated.…”

Section: Introductionmentioning

confidence: 99%

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Toll-like receptor 3 signaling induces apoptosis in human head and neck cancer via survivin associated pathway

Nomi

Kodama²,

Suzuki³

2010

Oncol Rep

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Abstract. The innate immune system builds up host defense against a huge diversity of pathogens, such as viruses, bacteria and fungi. Toll-like receptors (TLRs) are one of the pattern recognition receptors that trigger the initiation of various defense mechanisms. The expression of TLRs represents an important link between innate and adaptive immune responses. The expression of TLRs in several cancer cell types has been reported; however, the exact roles they play in cancers are still unclear. In this study, we investigated the expression and signaling of TLRs in human head and neck squamous cell carcinomas (HNSCCs). The expression of TLRs in 8 HNSCC cell lines was examined by Western blot analysis and flow cytometry. The expression of TLR mRNA was also examined by quantitative RT-PCR. Cells were incubated with poly I:C, a TLR3 ligand, and cell viability was tested by MTT assay. In addition, apoptosis was analyzed by flow cytometry with Annexin V and propidium iodide staining. The expression of survivin, a member of the inhibitors of the apoptosis protein family, was also investigated. TLR2 and TLR3 were widely expressed in human HNSCCs. Interestingly, the stimulation of TLR3 by poly I:C induced apoptosis in cancer cells in a dose-dependent manner. The expression of survivin was down-regulated during apoptosis, suggesting that TLR signaling affects survivinmediated signal transduction in apoptosis. In the present study, we demonstrated the proapoptotic activity of TLR3 expressed by HNSCCs. These results suggest that TLR3 could be a new target for therapy in HNSCCs.

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“…This trial did not however differentiate the role that Poly A:U and radiotherapy had as single therapies (Laplanche, 2000). Several studies have reported that caspase 3 is up-regulated by TLR3 agonist activity which would suggest a role for caspase 3 in cancer cell apoptosis induced by TLR3 agonists (Salaun, 2006;Khvalevsky, 2007). A recent study by Conforti et al demonstrated the synergistic effects between vaccines, chemotherapy and poly A:U (Conforti, 2010).…”

Section: Toll-like Receptor-3mentioning

confidence: 97%