The number and microlocalization of tumor-associated immune cells are associated with patient's survival time in non-small cell lung cancer

<p>Abstract</p> <p>Background</p> <p>Tumor microenvironment is composed of tumor cells, fibroblasts, endothelial cells, and infiltrating immune cells. Tumor-associated immune cells may inhibit or promote tumor growth and progression. This study was conducted to determine whether the number and microlocalization of macrophages, mature dendritic cells and cytotoxic T cells in non-small cell lung cancer are associated with patient's survival time.</p> <p>Methods</p> <p>Ninety-nine patients with non-small cell lung cancer (NSCLC) were included in this retrospective study. Paraffin-embedded NSCLC specimens and their clinicopathological data including up to 8-year follow-up information were used. Immunohistochemical staining for CD68 (marker for macrophages), CD83 (marker for mature dendritic cells), and CD8 (marker for cytotoxic T cells) was performed and evaluated in a blinded fashion. The numbers of immune cells in tumor islets and stroma, tumor islets, or tumor stroma were counted under a microscope. Correlation of the cell numbers and patient's survival time was analyzed using the Statistical Package for the Social Sciences (version 13.0).</p> <p>Results</p> <p>The numbers of macrophages, mature dendritic cells and cytotoxic T cells were significantly more in the tumor stroma than in the tumor islets. The number of macrophages in the tumor islets was positively associated with patient's survival time, whereas the number of macrophages in the tumor stroma was negatively associated with patient's survival time in both univariate and multivariate analyses. The number of mature dendritic cells in the tumor islets and stroma, tumor islets only, or tumor stroma only was positively associated with patient's survival time in a univariate analysis but not in a multivariate analysis. The number of cytotoxic T cells in the tumor islets and stroma was positively associated with patient's survival time in a univariate analysis but not in a multivariate analysis. The number of cytotoxic T cells in the tumor islets only or stroma only was not associated with patient's survival time.</p> <p>Conclusions</p> <p>The number of macrophages in the tumor islets or stroma is an independent predictor of survival time in NSCLC patients. Counting macrophages in the tumor islets or stroma is more useful in predicting patient's survival time than counting mature dendritic cells or cytotoxic T cells.</p

CircRNA ZKSCAN1 promotes lung adenocarcinoma progression by miR‐185‐5p/TAGLN2 axis

Abstract Background Circ‐ZKSCAN1 has been found to accelerate non‐small cell lung cancer (NSCLC) progression; however, the role and mechanism of circ‐ZKSCAN1 in lung adenocarcinoma (LUAD) cisplatin (DDP) resistance remain unclear. Methods Levels of genes and proteins were examined using qRT‐PCR. Functional experiments were performed using CCK‐8 assay, flow cytometry, transwell assay and xenograft model assay, respectively. Glucose metabolism was calculated by detecting glucose consumption, lactate production, ATP and HK‐2 levels. The interaction between miR‐185‐5p and circ‐ZKSCAN1 or transgelin 2 (TAGLN2) was validated by dual‐luciferase reporter assay. Results Circ‐ZKSCAN1 was highly expressed in DDP‐resistant LUAD tissues and cell lines, and circ‐ZKSCAN1 knockdown weakened DDP resistance and suppressed cell viability, migration, invasion, and glycolysis in LUAD. Circ‐ZKSCAN1 acted as a sponge of miR‐185‐5p, and the regulatory effects of circ‐ZKSCAN1 knockdown on LUAD were reversed by miR‐185‐5p downregulation. Meanwhile, miR‐185‐5p directly targeted TAGLN2, and performed anticancer effects by regulating TAGLN2. Importantly, silencing of circ‐ZKSCAN1 hindered tumor growth and promoted DDP sensitivity in vivo via regulating miR‐185‐5p and TAGLN2. Conclusion Circ‐ZKSCAN1 promoted LUAD tumorigenesis and DDP resistance by regulating miR‐185‐5p/TAGLN2 axis

The M1 form of tumor-associated macrophages in non-small cell lung cancer is positively associated with survival time

<p>Abstract</p> <p>Background</p> <p>Tumor-associated macrophages (TAMs) play an important role in growth, progression and metastasis of tumors. In non-small cell lung cancer (NSCLC), TAMs' anti-tumor or pro-tumor role is not determined. Macrophages are polarized into M1 (with anti-tumor function) and M2 (with pro-tumor function) forms. This study was conducted to determine whether the M1 and M2 macrophage densities in NSCLC are associated with patient's survival time.</p> <p>Methods</p> <p>Fifty patients with an average of 1-year survival (short survival group) and 50 patients with an average of 5-year survival (long survival group) were included in this retrospective study. Paraffin-embedded NSCLC specimens and their clinicopathological data including up to 8-year follow-up information were used. Immunohistochemical double-staining of CD68/HLA-DR (markers for M1 macrophages) and CD68/CD163 (markers for M2 macrophages) was performed and evaluated in a blinded fashion. The M1 and M2 macrophage densities in the tumor islets, stroma, or islets and stroma were determined using computer-aided microscopy. Correlation of the macrophage densities and patient's survival time was analyzed using the Statistical Package for the Social Sciences.</p> <p>Results</p> <p>Approximately 70% of TAMs were M2 macrophages and the remaining 30% were M1 macrophages in NSCLC. The M2 macrophage densities (approximately 78 to 113 per mm²) in the tumor islets, stroma, or islets and stroma were not significantly different between the long survival and short survival groups. The M1 macrophage densities in the tumor islets (approximately 70/mm²) and stroma (approximately 34/mm²) of the long survival group were significantly higher than the M1 macrophage densities in the tumor islets (approximately 7/mm²) and stroma (13/mm²) of the short survival group (P < 0.001 and P < 0.05, respectively). The M2 macrophage densities were not associated with patient's survival time. The M1 macrophage densities in the tumor islets, stroma, or islets and stroma were positively associated with patient's survival time in a univariate analysis (P < 0.01 or 0.001). In a multivariate Cox proportional hazards analysis, the M1 macrophage density in the tumor islets was an independent predictor of patient's survival time.</p> <p>Conclusions</p> <p>The M1 macrophage density in the tumor islets is an independent predictor of survival time in NSCLC patients.</p

A FAK Inhibitor Boosts Anti-PD1 Immunotherapy in a Hepatocellular Carcinoma Mouse Model

Anti-PD-1/PD-L1 immunotherapy has limited efficacy in hepatocellular carcinoma (HCC) and does not benefit all patients. A FAK inhibitor (VS-4718) has been reported to improve the microenvironment in some tumors. This study aimed to investigate the effect of the combination of the FAK inhibitor VS4718 and anti-PD1 for the treatment of HCC in a mouse model and its possible mechanism of action. The expression of FAK and infiltrated immune cells in human HCC from the data of TCGA were analyzed. A primary murine HCC model was established via protooncogene (c-Met/β-catenin) transfection. The pathological characteristics of tumors were examined after the mice were treated with VS4718 and/or anti-PD1 therapy. This study revealed that FAK is highly expressed in human HCC and is associated with poor prognosis of OS (overall survival) and PFS (progress free survival) in HCC patients. Immune cell infiltration (CD8+ T, Tregs, M0, M2, CAFs and MDSCs) was correlated with FAK expression. In the experimental HCC model, the combination of a FAK inhibitor VS4718 and an anti-PD1 antibody had a better effect than monotherapy against HCC. VS4718 reduced the number of Tregs and macrophages but increased the number of CD8+ T cells in HCC mice. Notably, FAK inhibitor promoted the expression of PD-L1 in HCC. This study suggested that combination of the FAK inhibitor VS4718 and anti-PD1 could be a potential therapy for HCC by improving the immune environment, reducing liver fibrosis and simultaneously preventing PD1 from binding to the increased PD-L1 induced by FAK inhibitor VS4718.</jats:p

DataSheet2_A FAK Inhibitor Boosts Anti-PD1 Immunotherapy in a Hepatocellular Carcinoma Mouse Model.ZIP

Anti-PD-1/PD-L1 immunotherapy has limited efficacy in hepatocellular carcinoma (HCC) and does not benefit all patients. A FAK inhibitor (VS-4718) has been reported to improve the microenvironment in some tumors. This study aimed to investigate the effect of the combination of the FAK inhibitor VS4718 and anti-PD1 for the treatment of HCC in a mouse model and its possible mechanism of action. The expression of FAK and infiltrated immune cells in human HCC from the data of TCGA were analyzed. A primary murine HCC model was established via protooncogene (c-Met/β-catenin) transfection. The pathological characteristics of tumors were examined after the mice were treated with VS4718 and/or anti-PD1 therapy. This study revealed that FAK is highly expressed in human HCC and is associated with poor prognosis of OS (overall survival) and PFS (progress free survival) in HCC patients. Immune cell infiltration (CD8+ T, Tregs, M0, M2, CAFs and MDSCs) was correlated with FAK expression. In the experimental HCC model, the combination of a FAK inhibitor VS4718 and an anti-PD1 antibody had a better effect than monotherapy against HCC. VS4718 reduced the number of Tregs and macrophages but increased the number of CD8+ T cells in HCC mice. Notably, FAK inhibitor promoted the expression of PD-L1 in HCC. This study suggested that combination of the FAK inhibitor VS4718 and anti-PD1 could be a potential therapy for HCC by improving the immune environment, reducing liver fibrosis and simultaneously preventing PD1 from binding to the increased PD-L1 induced by FAK inhibitor VS4718.</p

DataSheet1_A FAK Inhibitor Boosts Anti-PD1 Immunotherapy in a Hepatocellular Carcinoma Mouse Model.ZIP

Anti-PD-1/PD-L1 immunotherapy has limited efficacy in hepatocellular carcinoma (HCC) and does not benefit all patients. A FAK inhibitor (VS-4718) has been reported to improve the microenvironment in some tumors. This study aimed to investigate the effect of the combination of the FAK inhibitor VS4718 and anti-PD1 for the treatment of HCC in a mouse model and its possible mechanism of action. The expression of FAK and infiltrated immune cells in human HCC from the data of TCGA were analyzed. A primary murine HCC model was established via protooncogene (c-Met/β-catenin) transfection. The pathological characteristics of tumors were examined after the mice were treated with VS4718 and/or anti-PD1 therapy. This study revealed that FAK is highly expressed in human HCC and is associated with poor prognosis of OS (overall survival) and PFS (progress free survival) in HCC patients. Immune cell infiltration (CD8+ T, Tregs, M0, M2, CAFs and MDSCs) was correlated with FAK expression. In the experimental HCC model, the combination of a FAK inhibitor VS4718 and an anti-PD1 antibody had a better effect than monotherapy against HCC. VS4718 reduced the number of Tregs and macrophages but increased the number of CD8+ T cells in HCC mice. Notably, FAK inhibitor promoted the expression of PD-L1 in HCC. This study suggested that combination of the FAK inhibitor VS4718 and anti-PD1 could be a potential therapy for HCC by improving the immune environment, reducing liver fibrosis and simultaneously preventing PD1 from binding to the increased PD-L1 induced by FAK inhibitor VS4718.</p

Table1_A FAK Inhibitor Boosts Anti-PD1 Immunotherapy in a Hepatocellular Carcinoma Mouse Model.XLSX

Anti-PD-1/PD-L1 immunotherapy has limited efficacy in hepatocellular carcinoma (HCC) and does not benefit all patients. A FAK inhibitor (VS-4718) has been reported to improve the microenvironment in some tumors. This study aimed to investigate the effect of the combination of the FAK inhibitor VS4718 and anti-PD1 for the treatment of HCC in a mouse model and its possible mechanism of action. The expression of FAK and infiltrated immune cells in human HCC from the data of TCGA were analyzed. A primary murine HCC model was established via protooncogene (c-Met/β-catenin) transfection. The pathological characteristics of tumors were examined after the mice were treated with VS4718 and/or anti-PD1 therapy. This study revealed that FAK is highly expressed in human HCC and is associated with poor prognosis of OS (overall survival) and PFS (progress free survival) in HCC patients. Immune cell infiltration (CD8+ T, Tregs, M0, M2, CAFs and MDSCs) was correlated with FAK expression. In the experimental HCC model, the combination of a FAK inhibitor VS4718 and an anti-PD1 antibody had a better effect than monotherapy against HCC. VS4718 reduced the number of Tregs and macrophages but increased the number of CD8+ T cells in HCC mice. Notably, FAK inhibitor promoted the expression of PD-L1 in HCC. This study suggested that combination of the FAK inhibitor VS4718 and anti-PD1 could be a potential therapy for HCC by improving the immune environment, reducing liver fibrosis and simultaneously preventing PD1 from binding to the increased PD-L1 induced by FAK inhibitor VS4718.</p

DataSheet7_A FAK Inhibitor Boosts Anti-PD1 Immunotherapy in a Hepatocellular Carcinoma Mouse Model.ZIP

Anti-PD-1/PD-L1 immunotherapy has limited efficacy in hepatocellular carcinoma (HCC) and does not benefit all patients. A FAK inhibitor (VS-4718) has been reported to improve the microenvironment in some tumors. This study aimed to investigate the effect of the combination of the FAK inhibitor VS4718 and anti-PD1 for the treatment of HCC in a mouse model and its possible mechanism of action. The expression of FAK and infiltrated immune cells in human HCC from the data of TCGA were analyzed. A primary murine HCC model was established via protooncogene (c-Met/β-catenin) transfection. The pathological characteristics of tumors were examined after the mice were treated with VS4718 and/or anti-PD1 therapy. This study revealed that FAK is highly expressed in human HCC and is associated with poor prognosis of OS (overall survival) and PFS (progress free survival) in HCC patients. Immune cell infiltration (CD8+ T, Tregs, M0, M2, CAFs and MDSCs) was correlated with FAK expression. In the experimental HCC model, the combination of a FAK inhibitor VS4718 and an anti-PD1 antibody had a better effect than monotherapy against HCC. VS4718 reduced the number of Tregs and macrophages but increased the number of CD8+ T cells in HCC mice. Notably, FAK inhibitor promoted the expression of PD-L1 in HCC. This study suggested that combination of the FAK inhibitor VS4718 and anti-PD1 could be a potential therapy for HCC by improving the immune environment, reducing liver fibrosis and simultaneously preventing PD1 from binding to the increased PD-L1 induced by FAK inhibitor VS4718.</p