Targeting Tie-2/angiopoietin axis in experimental mesothelioma confers differential responses and raises predictive implications

Magkouta, Sophia; Pappas, Apostolos; Pateras, Ioannis S.; Kollintza, Androniki; Moschos, Charalampos; Vazakidou, Maria Eleni; Karavana, Vassiliki; Gorgoulis, Vassilis G.; Kalomenidis, Ioannis

doi:10.18632/oncotarget.25004

Cited by 7 publications

(5 citation statements)

References 28 publications

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“…Genes from the angiopoietins-tie pathway—which is critical for tumour angiogenesis—and CD31 ( PECAM1 in the gencode annotation; which is also a marker of angiogenesis) [31], [32] behave similarly to the “inducing angiogenesis” hallmark. Indeed, many of the genes in the angiopoietins-tie axis (including ANGPTL1, ANGPTL4 - 5, ANGPTL7, ANGPT1 - 2, ANGPT4 , and TIE1 ) belong to the genes with the largest molecular variation across samples (Table S2).…”

Section: Resultsmentioning

confidence: 99%

Redefining malignant pleural mesothelioma types as a continuum uncovers immune-vascular interactions

et al. 2019

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Background: Malignant Pleural Mesothelioma (MPM) is an aggressive disease related to asbestos exposure, with no effective therapeutic options. Methods: We undertook unsupervised analyses of RNA-sequencing data of 284 MPMs, with no assumption of discreteness. Using immunohistochemistry, we performed an orthogonal validation on a subset of 103 samples and a biological replication in an independent series of 77 samples. Findings: A continuum of molecular profiles explained the prognosis of the disease better than any discrete model. The immune and vascular pathways were the major sources of molecular variation, with strong differences in the expression of immune checkpoints and pro-angiogenic genes; the extrema of this continuum had specific molecular profiles: a "hot" bad-prognosis profile, with high lymphocyte infiltration and high expression of immune checkpoints and pro-angiogenic genes; a "cold" badprognosis profile, with low lymphocyte infiltration and high expression of pro-angiogenic genes; and a "VEGFR2+/VISTA+" better-prognosis profile, with high expression of immune checkpoint VISTA and proangiogenic gene VEGFR2. We validated the gene expression levels at the protein level for a subset of five selected genes belonging to the immune and vascular pathways (CD8A, PDL1, VEGFR3, VEGFR2, and VISTA), in the validation series, and replicated the molecular profiles as well as their prognostic value in the replication series. Interpretation: The prognosis of MPM is best explained by a continuous model, which extremes show specific expression patterns of genes involved in angiogenesis and immune response.

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Section: Resultsmentioning

confidence: 99%

Redefining malignant pleural mesothelioma types as a continuum uncovers immune-vascular interactions

et al. 2019

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“…HIF-1α signaling regulates chemotherapy-resistance, and the differentiation of immunosuppressive myeloid-derived suppressor cells (MDSCs) ( 43 ). Both AB1 and AE17 tumors display hypoxic regions in vivo ( 44 ), and chemo-immunotherapy could have altered tumor hypoxia. It is also possible that combination 5-FU and ICB alter tumor immunosuppressive cells through HIF-1α mediated pathways, resulting in decreased MDSCs and T regs observed in our study.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive Testing of Chemotherapy and Immune Checkpoint Blockade in Preclinical Cancer Models Identifies Additive Combinations

et al. 2022

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Antibodies that target immune checkpoints such as cytotoxic T lymphocyte antigen 4 (CTLA‐4) and the programmed cell death protein 1/ligand 1 (PD-1/PD-L1) are now a treatment option for multiple cancer types. However, as a monotherapy, objective responses only occur in a minority of patients. Chemotherapy is widely used in combination with immune checkpoint blockade (ICB). Although a variety of isolated immunostimulatory effects have been reported for several classes of chemotherapeutics, it is unclear which chemotherapeutics provide the most benefit when combined with ICB. We investigated 10 chemotherapies from the main canonical classes dosed at the clinically relevant maximum tolerated dose in combination with anti‐CTLA-4/anti-PD-L1 ICB. We screened these chemo-immunotherapy combinations in two murine mesothelioma models from two different genetic backgrounds, and identified chemotherapies that produced additive, neutral or antagonistic effects when combined with ICB. Using flow cytometry and bulk RNAseq, we characterized the tumor immune milieu in additive chemo-immunotherapy combinations. 5-fluorouracil (5-FU) or cisplatin were additive when combined with ICB while vinorelbine and etoposide provided no additional benefit when combined with ICB. The combination of 5-FU with ICB augmented an inflammatory tumor microenvironment with markedly increased CD8+ T cell activation and upregulation of IFNγ, TNFα and IL-1β signaling. The effective anti‐tumor immune response of 5-FU chemo-immunotherapy was dependent on CD8+ T cells but was unaffected when TNFα or IL-1β cytokine signaling pathways were blocked. Our study identified additive and non-additive chemotherapy/ICB combinations and suggests a possible role for increased inflammation in the tumor microenvironment as a basis for effective combination therapy.

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“…Immunoreactivity for IL-6 in the tumor cytoplasm was categorized as none/focal (0%–40%) or diffuse (50%–100%) 11 . Immunostaining for Ang1 was assessed in a semi-quantitative manner as previously described 38 . Tumor and stromal areas were evaluated independently and each section was assigned two scores: Staining intensity (0, no staining; 1, weak staining; 2, moderate staining; 3, intense staining) and proportion of cells stained (0, no cells staining; 1, 1%–25%; 2, 26%–50%; 3, 51%–75%; 4, 76%–100%).…”

Section: Methodsmentioning

confidence: 99%

Interleukin-6 as an enhancer of anti-angiogenic therapy for ovarian clear cell carcinoma

Seki

Yanaihara

Shapiro

et al. 2021

Sci Rep

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Ovarian clear cell carcinoma (OCCC) is a subtype of epithelial ovarian cancer (EOC) that is associated with elevated interleukin-6 (IL-6) expression, resistance to chemotherapy, and increased mortality. Although bevacizumab (Bev) is a widely used anti-angiogenic agent for EOC, the efficacy of Bev and the role of IL-6 in modulating angiogenesis in OCCC are unknown. We performed tube formation assays using human umbilical vein endothelial cells (HUVEC) cultured in OCCC cell-conditioned medium and using cells directly co-cultured with OCCC cells. We observed that IL-6 inhibition significantly mitigated the ability of Bev to impede tube formation in both cases. Furthermore, IL-6 blockade disrupted the anti-angiogenic efficacy of Bev and its concomitant anti-tumor activity. In addition, IL-6 inhibition resulted in a significant increase in angiopoietin-1 (Ang1) secretion and decreased vascular endothelial growth factor (VEGF) expression. Clinical specimens also exhibited this reciprocal relationship between IL-6 and Ang1 expression. Finally, depletion of Ang1 abrogated the effects of IL-6 inhibition on Bev activity, demonstrating that IL-6 supports the anti-angiogenic activity of Bev by suppressing Ang1 expression and promoting dependence on VEGF for angiogenesis. Altogether, our data suggest that OCCC tumors with high IL-6 levels are candidates for Bev therapy.

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Targeting Tie-2/angiopoietin axis in experimental mesothelioma confers differential responses and raises predictive implications

Cited by 7 publications

References 28 publications

Redefining malignant pleural mesothelioma types as a continuum uncovers immune-vascular interactions

Redefining malignant pleural mesothelioma types as a continuum uncovers immune-vascular interactions

Comprehensive Testing of Chemotherapy and Immune Checkpoint Blockade in Preclinical Cancer Models Identifies Additive Combinations

Interleukin-6 as an enhancer of anti-angiogenic therapy for ovarian clear cell carcinoma

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