Effect of TLR4 and B7-H1 on Immune Escape of Urothelial Bladder Cancer and its Clinical Significance

Wang, Yonghua; Cao, Yimei; Yang, Xuecheng; Niu, Haitao; Sun, Lili; Wang, Xinsheng; Liu, Jing

doi:10.7314/apjcp.2014.15.3.1321

Cited by 38 publications

(25 citation statements)

References 28 publications

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“…The global nature of this interaction is supported by the observation that an oncogenic role for TLR4 in tumor cells has been identified primarily in cancer types known to inactivate TP53 at high frequencies, such as ovarian (24), bladder (25), and head and neck (26) cancers. Further investigation is warranted in other cancer sites to define the association between TLR4 and TP53 and its effect on tumor biology and behavior.…”

Section: Discussionmentioning

confidence: 99%

TLR4 has a TP53-dependent dual role in regulating breast cancer cell growth

Haricharan

Brown

2015

Proc. Natl. Acad. Sci. U.S.A.

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Breast cancer is a leading cause of cancer-related death, and it is important to understand pathways that drive the disease to devise effective therapeutic strategies. Our results show that Toll-like receptor 4 (TLR4) drives breast cancer cell growth differentially based on the presence of TP53, a tumor suppressor. TP53 is mutationally inactivated in most types of cancer and is mutated in 30-50% of diagnosed breast tumors. We demonstrate that TLR4 activation inhibits growth of TP53 wild-type cells, but promotes growth of TP53 mutant breast cancer cells by regulating proliferation. This differential effect is mediated by changes in tumor cell cytokine secretion. Whereas TLR4 activation in TP53 mutant breast cancer cells increases secretion of progrowth cytokines, TLR4 activation in TP53 wild-type breast cancer cells increases type I IFN (IFN-γ) secretion, which is both necessary and sufficient for mediating TLR4-induced growth inhibition. This study identifies a novel dichotomous role for TLR4 as a growth regulator and a modulator of tumor microenvironment in breast tumors. These results have translational relevance, demonstrating that TP53 mutant breast tumor growth can be suppressed by pharmacologic TLR4 inhibition, whereas TLR4 inhibitors may in fact promote growth of TP53 wild-type tumors. Furthermore, using data generated by The Cancer Genome Atlas consortium, we demonstrate that the effect of TP53 mutational status on TLR4 activity may extend to ovarian, colon, and lung cancers, among others, suggesting that the viability of TLR4 as a therapeutic target depends on TP53 status in many different tumor types.reast cancer has one of the highest incidence rates of cancer in women worldwide, with more than 1.5 million women diagnosed with the disease in 2012. Owing to its high incidence, breast cancer is also one of the leading causes of cancer-related deaths, with 40,000 women predicted to die of the disease in 2014 in the US alone. The diagnosis and treatment of breast cancer has been significantly improved by the identification of three major subtypes of the disease based on receptor expression: estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-positive, and triple-negative [tumors lacking ER, progesterone receptor (PR), and HER2]. Of these subtypes, ER-positive breast cancer accounts for 70-80% of all diagnosed breast tumors.ER-positive breast cancer is largely responsive to endocrine therapy; however, intrinsic or acquired resistance occurs in onethird of cases and contributes significantly to breast cancerassociated mortality. Therefore, identifying therapeutic targets to prevent ER-positive breast cancer mortality is a major focus of scientific investigation. ER-positive breast tumors with a high mutation load are associated with poor patient survival, and a high mutation load likely affects the response to endocrine therapy (1). Because known drivers of endocrine resistance (e.g., PR negativity and HER2 amplification) are not enriched in this subset, the identification of no...

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Section: Discussionmentioning

confidence: 99%

TLR4 has a TP53-dependent dual role in regulating breast cancer cell growth

Haricharan

Brown

2015

Proc. Natl. Acad. Sci. U.S.A.

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“…This delayed tumor-inhibiting effects in VSIG4 À / À mice might reflect the fact that there are other immune-inhibiting molecules in vivo besides VSIG4. 6,7 The deficiency of VSIG4 might remove partial inhibition effects to host immune responses; however, other inhibitory molecules would partially compensate the function of VSIG4, which would cause the significant but delayed inhibition of tumor growth in VSIG4 À / À mice.…”

Section: Vsig4 Promotes Lung Cancer Development Y Liao Et Almentioning

confidence: 99%

“…In addition, the newly defined B7 family members PD-L1 (B7-H1), PD-L2 (B7-DC), B7-H3, and B7-H4 (B7x/B7-S1) are expressed on professional APCs as well as on cells within nonlymphoid organs, providing new means for downregulating T-cell activation and maintaining tolerance in peripheral tissues by serving as ligands of CD28. 7 Disruption of negative T-cell immunomodulatory pathways, using targeted disruption of gene expression, monoclonal antibodies, or soluble receptors that neutralize the coinhibitory signals, can overcome T-cell tolerance and generate effective antitumor responses. 8,9 Coinhibitory signals have been implicated in the development of lung cancer.…”

mentioning

confidence: 99%

VSIG4 expression on macrophages facilitates lung cancer development

Liao

Guo

Chen

et al. 2014

Laboratory Investigation

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Tumor-associated macrophages are a prominent component of lung cancer stroma and contribute to tumor progression. The protein V-set and Ig domain-containing 4 (VSIG4), a novel B7 family-related macrophage protein that has the capacity to inhibit T-cell activation, has a potential role in the development of lung cancer. In this study, 10 human non-small-cell lung cancer specimens were collected and immunohistochemically analyzed for VSIG4 expression. Results showed massive VSIG4 þ cell infiltration throughout the samples. Immunofluorescent double staining showed that VSIG4 was present on CD68 þ macrophages, but absent from CD3 þ T cells, CD31 þ endothelial cells, and CK-18 þ epithelial cells. Moreover, VSIG4 was coexpressed on B7-H1 þ and B7-H3 þ cells in these tumor specimens. Transfection of the VSIG4 gene into 293FT cells demonstrated that the VSIG4 signal could inhibit cocultured CD4 þ and CD8 þ T-cell proliferation and cytokine (IL-2 and IFN-g) production in vitro. Interestingly, in a murine tumor model induced by Lewis lung carcinoma cell line, we found that tumors grown in VSIG4-deficient (VSIG4 À / À ) mice were significantly smaller than those found in wildtype littermates. All of these results demonstrate that macrophage-associated VSIG4 is an activator that facilitates lung carcinoma development. Specific targeting of VSIG4 may prove to be a novel, efficacious strategy for the treatment of this carcinoma.

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“…By contrast, patients with high-grade NMIBC exhibit significantly higher expression rates of PD-L1 and PD-1. Expression of PD-1 on tumor-infiltrating lymphocytes (TILs) and B7-H1 on tumor cells showed a direct correlation [35]. Figure 1 outlines the interaction between cell surface proteins PD-1 and PD-L1 on lymphocytes and tumor cells.…”

Section: Escape Mechanisms Of Urothelial Cancer Cellsmentioning

confidence: 96%

“…Toll-like receptor 4 (TLR4) represents a member of the Toll-like receptor family which functions as a lipopolysaccharide (LPS) signaling receptor in urinary tract infections. An excessive release of LPS during septicemia (i.e., caused by an Escherichia coli infection) can enhance TLR4 signaling [35][36][37]. TLR4, originally found as an epitope on immune cells, has also been detected on tumor cells and is assumed to induce signaling pathways which protect tumor cells from the immune system [38].…”

Section: Escape Mechanisms Of Urothelial Cancer Cellsmentioning

confidence: 99%

Inflammation and Cancer: What Can We Therapeutically Expect from Checkpoint Inhibitors?

et al. 2015

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Programmed death-ligand 1 (PD-L1) is a cell surface protein which is mainly expressed on immune cells as well as on cancer cells and functions as a co-stimulatory molecule for T lymphocytes. It is capable of inducing apoptosis in T-cells via PD-1 which leads to impaired cytokine production and loss of cytotoxicity of activated T-cells. This represents a possible escape mechanism for cancer cells. Tumor infiltration by mononuclear cells and tumor aggressiveness was found to be associated with PD-L1 expression. In light of possible autoimmunological side effects, it remains currently unclear which patient will benefit most from this novel therapeutic approach. Furthermore, immunohistochemistry for PD-L1 has not been well standardized until now. In addition, the combination of chemotherapy with checkpoint inhibitors in different clinical settings needs to be established for the near future in order to avoid overtreatment and also unnecessary cost expenditures for the health care system.

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Effect of TLR4 and B7-H1 on Immune Escape of Urothelial Bladder Cancer and its Clinical Significance

Cited by 38 publications

References 28 publications

TLR4 has a TP53-dependent dual role in regulating breast cancer cell growth

TLR4 has a TP53-dependent dual role in regulating breast cancer cell growth

VSIG4 expression on macrophages facilitates lung cancer development

Inflammation and Cancer: What Can We Therapeutically Expect from Checkpoint Inhibitors?

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