scholarly journals 263 ASD141, an innate checkpoint inhibitor, modulates tumor associated myeloid cells through CD11b and enhances current immune checkpoint blockade in preclinical model

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A285-A285
Author(s):  
Chia-Ming Chang ◽  
Jason (Ping-Yen) Huang ◽  
I-Fang Tsai ◽  
Yen-Ta Lu
Keyword(s):  
Colon Cancer ◽  
Dendritic Cells ◽  
Tumor Growth ◽  
Immune Checkpoint ◽  
Critical Role ◽  
Myeloid Cells ◽  
Peripheral Tolerance ◽  
High Avidity ◽  
Chimeric Mouse ◽  
The Impact

BackgroundTumor-associated myeloid cells (TAMCs) are a heterogeneous population of myeloid cells present in the tumor microenvironment (TME). They contribute to immunosuppression and growth of solid tumor. These myeloid cells are highly expressed with CD11b, the alpha-chain of integrin receptor alphaMbeta2 (also known as CD11b/CD18, Mac-1, CR3). It has been suggested that activation of CD11b could facilitate the development of peripheral tolerance by inhibiting T helper 17 differentiation. Antigen-presenting cells (dendritic cells and macrophages) have been shown to enhance T cell proliferation with the treatment of anti-CD11b antibody. Furthermore, CD11b plays a critical role in inflammation by modulating Toll-Like receptor (TLR) responses. High avidity activated form of CD11b leads to a rapid inhibition of TLR signaling by promoting degradation of MyD88 and TRIFs. Therefore, CD11b may serve as an innate checkpoint that function as a negative immune regulator.MethodsIn order to investigate the impact of CD11b in modulating the TME and tumor growth, ASCENDO Biotechnology generated a surrogate chimeric mouse IgG1 antibody, mouse ASD141 (Xi2396), which targets mouse CD11b. These antibodies were then tested in murine MC38 colon cancer.ResultsMouse ASD141 as monotherapy results in statistically significant growth inhibition in murine colon cancer models. Xi2396 remodels the TME by decreasing infiltration of TAMCs, and increased infiltration of dendritic cells (cDCs, NKDCs, and pDCs). Furthermore, Xi2396 also enhanced the antigen presentation ability, which is accompanied by an increased expression of MHCII, CD80 and CD86. These results indicate that the anti-CD11b monoclonal antibody, ASD141, designed to modulate TAMCs of the TME represents a novel approach of cancer immunotherapy.Xi2396 treatment also induced high levels of PD-L1 expression in the TME. Since PD-L1 expression in the TME was associated with response to current immune checkpoint blockades, we sought to determine whether Xi2396 treatment is capable of enhancing anti-tumor response to anti-PD1 therapy. Our results showed that combination of Xi2396 and anti-PD1 synergistically suppressed tumor growth.ConclusionsAltogether, our results provide support for clinical efforts to evaluate ASD141 as an innate immune checkpoint drug, especially in combination with commercial immune checkpoint inhibitors.Ethics ApprovalThis study was approved by National Laboratory Animal Center‘s Institutional Animal Care and Use Committee; approval number NLAC-110-D-006-R2.

scholarly journals Murine hepatoma treatment with mature dendritic cells stimulated by Trichinella spiralis excretory/secretory products

Parasite ◽  
2020 ◽  
Vol 27 ◽  
pp. 47
Author(s):  
Jing Ding ◽  
Xiaolei Liu ◽  
Bin Tang ◽  
Xue Bai ◽  
Yang Wang ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Tumor Growth ◽  
Antitumor Effect ◽  
Trichinella Spiralis ◽  
Critical Role ◽  
Tumor Model ◽  
Control Group ◽  
Tumor Inhibition ◽  
Significant Difference ◽  
Secretory Products

Excretory/Secretory Products (ESPs) of the nematode Trichinella spiralis contain antitumor-active substances that inhibit tumor growth. Mature dendritic cells (DCs) play a critical role in the antitumor immunity of the organism. As pathogen-derived products, it ought to be discussed whether T. spiralis ESPs will reduce the antitumor effect of mature DCs from the host before it is applied to patients’ tumors. Therefore, the aim of this work was to evaluate the immunological effect of DCs stimulated by T. spiralis ESPs in H22 tumor-bearing mice. H22 tumor model mice in this study were randomly divided into four groups according to the treatment: PBS control group, ESP group, DCs group, and DCs stimulated with T. spiralis ESP (ESP+DCs group). The antitumor effect was evaluated by tumor inhibition rate and cytokine detection using ELISA. The results showed significant inhibition in tumor growth in the ESP+DCs, DCs and ESP groups when compared with the PBS control group (p < 0.01, p < 0.01, and p < 0.05, respectively). However, no significant difference was observed on tumor inhibition rates between the ESP+DCs and DCs groups. The decrease in IL-4, IL-6, and IL-10, and the increase in IFN-γ between the DCs and ESP+DCs groups were also not significant. Therefore, DCs stimulated by ESP did not reduce the antitumor effect of mature DCs, which demonstrated that the T. spiralis ESP would not affect the antitumor effect of mature DCs by modulating the immune response of the host, and that ESPs are safe in antitumor immunology when applied in a tumor model mice.

Abstract 19409: β2-Adrenergic Receptor Regulation of Innate Immune Responses Following Acute Myocardial Injury

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Laurel A Grisanti ◽  
Anna Gumpert ◽  
Joshua Gorsky ◽  
Ashley A Repas ◽  
Erhe Gao ◽  
...  
Keyword(s):  
Immune Responses ◽  
Adrenergic Receptor ◽  
Inflammatory Responses ◽  
Critical Role ◽  
Cellular Migration ◽  
Chimeric Mouse ◽  
Ccr2 Expression ◽  
Β2 Adrenergic Receptor ◽  
The Impact

Inflammatory responses are important for cardiac remodeling and tissue repair after myocardial infarction (MI). The sympathetic nervous system is known to regulate immune responses, in large part through the β2-adrenergic receptor (β2AR), however the influence of β2AR in regulating the inflammatory response following MI is unknown. Thus, to examine the contribution of β2AR on immune cells following MI, wild-type (WT) mice were irradiated and then received β2ARKO or WT control bone marrow (BM) transplants to create immune cell-specific knockout (KO) animals. Lack of β2AR expression in BM resulted in 100% mortality from cardiac rupture within two weeks of receiving MI, in contrast to their WT counterparts that had ∼20% death. Granulocyte populations were sequestered in the spleen of β2ARKO chimeric mice resulting in reductions in post-MI infiltration of monocyte/macrophage, neutrophil and mast cell populations into the heart. Additionally, alterations in chemokine receptor levels, particularly CCR2, on BM resulted in decreased cellular migration, and use of a CCR2 antagonist in vivo recapitulated the β2ARKO chimeric mouse phenotype following MI. Administration of β2AR agonists in vitro and in vivo increased CCR2 expression and BM migration while β2AR antagonists decreased CCR2 expression and increased splenic leukocyte retention in vivo . Use of pepducins as allosteric modulators of β2AR signaling demonstrated the importance of β-arrestin-mediated signaling in increasing CCR2 expression and responses. The impact of β2AR deletion on BM cell CCR2 expression and migration, splenic retention of leukocytes and reciprocal cardiac leukocyte infiltration following MI could be reversed via lentivirus-mediated β2AR rescue in the β2ARKO BM prior to transplantation. These results demonstrate the critical role of β2AR in the regulation of CCR2 expression on hematopoietic cells and its importance in mounting an immune response to promote healing following acute cardiac injury.

scholarly journals NF-κB p50-deficient immature myeloid cell (p50-IMC) adoptive transfer slows the growth of murine prostate and pancreatic ductal carcinoma

2020 ◽  
Vol 8 (1) ◽  
pp. e000244 ◽  
Author(s):  
Rahul Suresh ◽  
David J Barakat ◽  
Theresa Barberi ◽  
Lei Zheng ◽  
Elizabeth Jaffee ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Tumor Growth ◽  
T Cell Activation ◽  
Adoptive Transfer ◽  
Cell Activation ◽  
Ductal Carcinoma ◽  
Myeloid Cells ◽  
Pancreatic Ductal Carcinoma ◽  
Immature Myeloid Cells

BackgroundMacrophages and dendritic cells lacking the transcription factor nuclear factor kappa B p50 are skewed toward a proinflammatory phenotype, with increased cytokine expression and enhanced T cell activation; additionally, murine melanoma, fibrosarcoma, colon carcinoma, and glioblastoma grow slower in p50−/−mice. We therefore evaluated the efficacy of p50-negative immature myeloid cells (p50-IMCs) adoptively transferred into tumor-bearing hosts. Immature cells were used to maximize tumor localization, and pretreatment with 5-fluorouracil (5FU) was examined due to its potential to impair marrow production of myeloid cells, to target tumor myeloid cells and to release tumor neoantigens.MethodsWild-type (WT)-IMC or p50-IMC were generated by culturing lineage-negative marrow cells from WT or p50−/−mice in media containing thrombopoietin, stem cell factor and Flt3 ligand for 6 days followed by monocyte colony-stimulating factor for 1 day on ultralow attachment plates. Mice inoculated with Hi-Myc prostate cancer (PCa) cells or K-RasG12Dpancreatic ductal carcinoma (PDC)-luciferase cells received 5FU followed 5 days later by three doses of 107immature myeloid cells (IMC) every 3–4 days.ResultsPCa cells grew slower in p50−/−mice, and absence of host p50 prolonged the survival of mice inoculated orthotopically with PDC cells. IMC from Cytomegalovirus (CMV)-luciferase mice localized to tumor, nodes, spleen, marrow, and lung. 5FU followed by p50-IMC slowed PCa and PDC tumor growth, ~3-fold on average, in contrast to 5FU followed by WT-IMC, 5FU alone or p50-IMC alone. Slowed tumor growth was evident for 93% of PCa but only 53% of PDC tumors; we therefore focused on PCa for additional IMC analyses. In PCa, p50-IMC matured into F4/80+macrophages, as well as CD11b+F4/80−CD11c+conventional dendritic cells (cDCs). In both tumor and draining lymph nodes, p50-IMC generated more macrophages and cDCs than WT-IMC. Activated tumor CD8+T cells were increased fivefold by p50-IMC compared with WT-IMC, and antibody-mediated CD8+T cell depletion obviated slower tumor growth induced by 5FU followed by p50-IMC.Conclusions5FU followed by p50-IMC slows the growth of murine prostate and pancreatic carcinoma and depends on CD8+T cell activation. Deletion of p50 in patient-derived marrow CD34+cells and subsequent production of IMC for adoptive transfer may contribute to the therapy of these and additional cancers.

The critical role of dysregulated FOXM1–PLAUR signaling in human colon cancer progression and metastasis.

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 405-405
Author(s):  
Dawei Li ◽  
Ping Wei ◽  
Zhihai Peng ◽  
Chen Huang ◽  
Huamei Tang ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Cancer Progression ◽  
Cancer Biology ◽  
Critical Role ◽  
Cox Proportional Hazards Model ◽  
Urokinase Plasminogen Activator Receptor ◽  
Altered Expression ◽  
Colon Cancer Progression ◽  
Foxm1 Expression ◽  
The Impact

405 Background: The mammalian Forkhead Box (Fox) transcription factor FOXM1 is implicated in tumorigenesis including mouse intestinal cancer. However, the clinical significance of FOXM1 signaling in human colorectal cancer (CRC) pathogenesis remains unknown. Methods: We investigated FOXM1 expression in 203 cases of primary colon cancer and matched normal colon tissue specimens and explored the underlying mechanisms of altered FOXM1 expression and the impact of this altered expression on colon cancer growth and metastasis using in vitro and animal models of colon cancer. Results: We found weak expression of FOXM1 protein in the colon mucosa, whereas we observed strong FOXM1 expression in tumor-cell nuclei of colon cancer and lymph node metastases. A Cox proportional hazards model revealed that FOXM1 expression was an independent prognostic factor in multivariate analysis. Experimentally, overexpression of FOXM1 by gene transfer significantly promoted the growth and metastasis of colon cancer cells in orthotopic mouse models, whereas knockdown of FOXM1 expression by small interfering RNA did the opposite. Promotion of colon tumorigenesis by FOXM1 directly and significantly correlated with activation of urokinase plasminogen activator receptor (PLAUR) expression and elevation of invasion and metastasis. Conclusions: Given the importance of FOXM1 in regulation of the expression of genes key to cancer biology, dysregulated expression and activation of FOXM1 may play important roles in colon cancer progression and metastasis.

A retrospective analysis on the impact of preoperative neutrophil to lymphocyte ratio in stage II colon cancer.

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 794-794
Author(s):  
Deepna Jaiswal ◽  
Suparna Mantha ◽  
Lucas Wong ◽  
Luis Seija ◽  
Yolanda Munoz
Keyword(s):  
Colon Cancer ◽  
Overall Survival ◽  
Adjuvant Chemotherapy ◽  
Critical Role ◽  
Univariate Analysis ◽  
Neutrophil To Lymphocyte Ratio ◽  
Stage Ii ◽  
Lymphocyte Ratio ◽  
Stage Ii Colon Cancer ◽  
The Impact

794 Background: Inflammation has a critical role in tumor genesis and progression of cancer. The neutrophil to lymphocyte ratio (NLR) is an indication of balance between the immune systems pro and defense mechanism against cancer. Elevated NLR is of interest in many cancers, including colon cancer. Although surgery is the mainstay of treatment for early stage colon cancer, adjuvant chemotherapy for stage II colon cancer has remained debatable. We proposed to study the impact of the NLR in patients with stage II colon cancer and to identify high risk patients who would benefit from adjuvant chemotherapy. Methods: Three hundred and eighty patients diagnosed with Stage II colon cancer at our institution were included in this retrospective study. Kaplan-Meir curves and multivariate Cox-regression analyses were calculated for overall survival. Results: Univariate analysis showed NLR was not statistically significant as predictor of mortality (p-value=0.0857). However, after adjusting for recurrence, chemotherapy, age, white blood cell count, the NLR was predictive for survival, with a hazard ratio of 1.05 and 95% confidence interval of (1.006 - 1.1). Recurrence and age were also significant predictors of survival (p-values of <0.0001 for both), and HR of 3.1 (2.0 – 4.6) and 1.4 (1.2 – 1.5), respectively. Conclusions: The neutrophil to lymphocyte ratio might be an independent prognostic marker for overall survival in stage II colon cancer patients. Given the retrospective nature of our study, further studies are indicated to confirm our findings.

Peripheral tolerance by Treg via constraining OX40 signal in autoreactive T cells against desmoglein 3, a target antigen in pemphigus

2021 ◽  
Vol 118 (49) ◽  
pp. e2026763118
Author(s):  
Hisato Iriki ◽  
Hayato Takahashi ◽  
Naoko Wada ◽  
Hisashi Nomura ◽  
Miho Mukai ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Peripheral Tolerance ◽  
Target Antigen ◽  
High Avidity ◽  
Dependent Manner ◽  
Autoreactive T Cells ◽  
Desmoglein 3

Antigen-specific peripheral tolerance is crucial to prevent the development of organ-specific autoimmunity. However, its function decoupled from thymic tolerance remains unclear. We used desmoglein 3 (Dsg3), a pemphigus antigen expressed in keratinocytes, to analyze peripheral tolerance under physiological antigen-expression conditions. Dsg3-deficient thymi were transplanted into athymic mice to create a unique condition in which Dsg3 was expressed only in peripheral tissue but not in the thymus. When bone marrow transfer was conducted from high-avidity Dsg3-specific T cell receptor–transgenic mice to thymus-transplanted mice, Dsg3-specific CD4+ T cells developed in the transplanted thymus but subsequently disappeared in the periphery. Additionally, when Dsg3-specific T cells developed in Dsg3−/− mice were adoptively transferred into Dsg3-sufficient recipients, the T cells disappeared in an antigen-specific manner without inducing autoimmune dermatitis. However, Dsg3-specific T cells overcame this disappearance and thus induced autoimmune dermatitis in Treg-ablated recipients but not in Foxp3-mutant recipients with dysfunctional Tregs. The molecules involved in disappearance were sought by screening the transcriptomes of wild-type and Foxp3-mutant Tregs. OX40 of Tregs was suggested to be responsible. Consistently, when OX40 expression of Tregs was constrained, Dsg3-specific T cells did not disappear. Furthermore, Tregs obtained OX40L from dendritic cells in an OX40-dependent manner in vitro and then suppressed OX40L expression in dendritic cells and Birc5 expression in Dsg3-specific T cells in vivo. Lastly, CRISPR/Cas9-mediated knockout of OX40 signaling in Dsg3-specific T cells restored their disappearance in Treg-ablated recipients. Thus, Treg-mediated peripheral deletion of autoreactive T cells operates as an OX40-dependent regulatory mechanism to avoid undesired autoimmunity besides thymic tolerance.

A retrospective analysis on the impact of preoperative neutrophil to lymphocyte ratio in stage II colon cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e15146-e15146
Author(s):  
Deepna Deepak Jaiswal ◽  
Suparna Mantha ◽  
Luis Seija ◽  
Yolanda Munoz ◽  
Lucas Wong
Keyword(s):  
Colon Cancer ◽  
Overall Survival ◽  
Adjuvant Chemotherapy ◽  
Critical Role ◽  
Univariate Analysis ◽  
Neutrophil To Lymphocyte Ratio ◽  
Stage Ii ◽  
Lymphocyte Ratio ◽  
Stage Ii Colon Cancer ◽  
The Impact

e15146 Background: Inflammation has a critical role in tumor genesis and progression of cancer. The neutrophil to lymphocyte ratio (NLR) is an indication of balance between the immune systems pro and defense mechanism against cancer. Elevated NLR is of interest in many cancers, including colon cancer. Although surgery is the mainstay of treatment for early stage colon cancer, adjuvant chemotherapy for stage II colon cancer has remained debatable. We proposed to study the impact of the NLR in patients with stage II colon cancer and to identify high risk patients who would benefit from adjuvant chemotherapy. Methods: Three hundred and eighty patients diagnosed with Stage II colon cancer at our institution were included in this retrospective study. Kaplan-Meir curves and multivariate Cox-regression analyses were calculated for overall survival. Results: Univariate analysis showed NLR was not statistically significant as predictor of mortality (p-value = 0.0857). However, after adjusting for recurrence, chemotherapy, age, white blood cell count, the NLR was predictive for survival, with a hazard ratio of 1.05 and 95% confidence interval of (1.006 - 1.1). Recurrence and age were also significant predictors of survival (p-values of < 0.0001 for both), and HR of 3.1 (2.0 – 4.6) and 1.4 (1.2 – 1.5), respectively. Conclusions: The neutrophil to lymphocyte ratio might be an independent prognostic marker for overall survival in stage II colon cancer patients. Given the retrospective nature of our study, further studies are indicated to confirm our findings.

Association of genetic variations within the PD-L2 immune checkpoint gene with outcome in stage II and III colon cancer.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 626-626
Author(s):  
Martin D. Berger ◽  
Inti Zlobec ◽  
Dongyun Yang ◽  
Shu Cao ◽  
Yu Sunakawa ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Cancer Patients ◽  
Recurrence Rate ◽  
Immune Checkpoint ◽  
Multivariate Analyses ◽  
Stage Ii ◽  
Stage Iii ◽  
Immune Checkpoints ◽  
High Recurrence Rate ◽  
The Impact

626 Background: Immune checkpoints can either inhibit or stimulate T-cell responses and therefore play a key role in maintaining an equilibrium between self tolerance and autoimmunity. Targeting immune checkpoint molecules can result in increased antitumor immunity by stimulation of the immune system. We hypothesize, that variations in genes encoding for both inhibitory or stimulatory immune checkpoint proteins may predict outcome in stage II and III colon cancer patients. Methods: The impact of 6 functional single nucleotide polymorphisms (SNPs) within the PD1, PD-L1, PD-L2, TIM3, OX40 and CD27 genes on time to recurrence was evaluated in 201 patients with stage II and III colon cancer. Genomic DNA was extracted from formalin-fixed paraffin embedded tissue and the SNPs were analyzed by PCR-based direct sequencing. Results: Baseline characteristics were as follows: female/male ratio = 42.8% / 57.2%; median age = 70y (19-91); median follow-up = 43months. The PD-L2 rs16923189 SNP showed significant association with recurrence rate. Patients with a G/G genotype had a higher 3-years recurrence rate compared to those harboring any A allele (41% vs 19%) in both univariate (HR 2.68, 95% Confidence interval (CI) 1.28-5.61, p = 0.006) and multivariate analyses (HR 3.13, 95% CI 1.42-6.28, p = 0.003). The high recurrence rate was most evident among patients with stage III and left-sided tumors carrying the G/G genotype (53% vs 24% and 65% vs 18%) in both univariate (HR 2.87, 95% CI 1.24-6.66, p = 0.009 and HR 5.28, 95% CI 2.24-12.44, p < 0.0001) and multivariate analyses (HR 4.32, 95% CI 1.76-9.91, p = 0.001 and HR 5.20, 95% CI 2.02-12.75, p = 0.001). Conclusions: Our results provide the first evidence, that polymorphisms within the PD-L2 gene might serve as prognostic markers in patients with stage II and III colon cancer. Interestingly, the prognostic effect is most significant among patients with stage III and left-sided colon cancers. Targeting PD-L2 might be a promising approach to further optimize treatment options and to improve outcome of colon cancer patients in the adjuvant setting.

Impact of Proton Pump Inhibitor Use on the Effectiveness of Immune Checkpoint Inhibitors in Advanced Cancer Patients

2021 ◽  
pp. 106002802110339
Author(s):  
Kangning Peng ◽  
Ken Chen ◽  
Benjamin A. Teply ◽  
Gary C. Yee ◽  
Paraskevi A. Farazi ◽  
...  
Keyword(s):  
Cell Carcinoma ◽  
Cancer Patients ◽  
Advanced Cancer ◽  
Proton Pump ◽  
Gut Microbiome ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Critical Role ◽  
The Impact

Background: The gut microbiome plays a critical role in modulating the therapeutic effect of immune checkpoint inhibitors (ICIs). Proton pump inhibitors (PPIs) are commonly used in cancer patients and may affect the gut microbiome by altering gut pH. Objective: To evaluate if concurrent use of PPI is associated with overall survival (OS) and progression-free survival (PFS) in patients with stage IV non–small-cell lung cancer (NSCLC), melanoma, renal cell carcinoma, transitional cell carcinoma, or head and neck squamous cell carcinoma. Methods: This was a single-center retrospective cohort study of advanced cancer adult patients who received nivolumab or pembrolizumab between September 1, 2014, and August 31, 2019. Concomitant PPI exposure was defined as PPI use 0 to 30 days before or after initiation of ICIs. Treatment outcome was OS and PFS. Results: A total of 233 patients were included in our study. Concomitant PPI use was not significantly associated with OS (hazard ratio [HR] = 1.22; 95% CI = 0.80-1.86) or PFS (HR = 1.05; 95% CI = 0.76-1.45) in patients with ICI use. The effect estimates were robust after adjusting for covariates in multivariate analysis and in patients with NSCLC. Conclusion and Relevance: Concomitant PPI use was not associated with the effectiveness of nivolumab or pembrolizumab. Certain predictors of survival outcomes related to PPI use in patients receiving immunotherapy, such as the time window and indication of PPI exposure and autoimmune disorders, should be explored in the future to better carve out the impact of PPI on the effectiveness of ICI use.

scholarly journals Inhibition of TLR4 Signaling Impedes Tumor Growth in Colitis-Associated Colon Cancer

2021 ◽  
Vol 12 ◽  
Author(s):  
Eva Pastille ◽  
Tabea Faßnacht ◽  
Alexandra Adamczyk ◽  
Nhi Ngo Thi Phuong ◽  
Jan Buer ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Tumor Growth ◽  
Pathogenic Bacteria ◽  
Intestinal Inflammation ◽  
Specific Inhibitor ◽  
Body Weight Loss ◽  
Tlr4 Signaling ◽  
Novel Approach ◽  
Increased Risk ◽  
The Impact

Patients suffering from ulcerative colitis are at increased risk of developing colorectal cancer. Although the exact underlying mechanisms of inflammation-associated carcinogenesis remain unknown, the intestinal microbiota as well as pathogenic bacteria are discussed as contributors to inflammation and colitis-associated colon cancer (CAC). In the present study, we analyzed the impact of TLR4, the receptor for Gram-negative bacteria derived lipopolysaccharides, on intestinal inflammation and tumorigenesis in a murine model of CAC. During the inflammatory phases of CAC development, we observed a strong upregulation of Tlr4 expression in colonic tissues. Blocking of TLR4 signaling by a small-molecule-specific inhibitor during the inflammatory phases of CAC strongly diminished the development and progression of colonic tumors, which was accompanied by decreased numbers of infiltrating macrophages and reduced colonic pro-inflammatory cytokine levels compared to CAC control mice. Interestingly, inhibiting bacterial signaling by antibiotic treatment during the inflammatory phases of CAC also protected mice from severe intestinal inflammation and almost completely prevented tumor growth. Nevertheless, application of antibiotics involved rapid and severe body weight loss and might have unwanted side effects. Our results indicate that bacterial activation of TLR4 on innate immune cells in the colon triggers inflammation and promotes tumor growth. Thus, the inhibition of the TLR4 signaling during intestinal inflammation might be a novel approach to impede CAC development.

Sign in / Sign up

Export Citation Format

Share Document