Regulating monocyte infiltration and differentiation: Providing new therapies for colorectal cancer patients with COVID-19.
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ABSTRACT:
SUBMITTER: Bai L
PROVIDER: S-EPMC8686133 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Tumor-associated macrophages often correlate with tumor progression, and therapies targeting immune cells in tumors have emerged as promising treatments. To select effective therapies, we established an in vitro 3D multicellular spheroid model including cancer cells, fibroblasts, and monocytes. We analyzed monocyte infiltration and differentiation in spheroids generated from fibroblasts and either of the cancer cell lines MCF-7, HT-29, PANC-1, or MIA PaCa-2. Monocytes rapidly infiltrated spheroids and differentiated into mature macrophages with diverse phenotypes in a cancer cell line-dependent manner. MIA PaCa-2 spheroids polarized infiltrating monocytes to M2-like macrophages with high CD206 and CD14 expression, whereas monocytes polarized by MCF-7 spheroids displayed an M1-like phenotype. Monocytes in HT-29 and PANC-1 primarily obtained an M2-like phenotype but also showed upregulation of M1 markers. Analysis of the secretion of 43 soluble factors demonstrated that the cytokine profile between spheroid cultures differed considerably depending on the cancer cell line. Secretion of most of the cytokines increased upon the addition of monocytes resulting in a more inflammatory and pro-tumorigenic environment. These multicellular spheroids can be used to recapitulate the tumor microenvironment and the phenotype of tumor-associated macrophages in vitro and provide more realistic 3D cancer models allowing the in vitro screening of immunotherapeutic compounds.
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Project description:Background and purposeNew therapies for inflammatory bowel disease (IBD) are highly desirable. As apolipoprotein (apo)A-I mimetic peptides are beneficial in several animal models of inflammation, we hypothesized that they might be effective at inhibiting murine colitis.Experimental approachDaily injections of 5A peptide, a synthetic bihelical apoA-I mimetic dissolved in PBS, or PBS alone were administered to C57BL/6 mice fed 3% (w v(-1) ) dextran sodium sulfate (DSS) in drinking water or healthy controls.Key resultsDaily treatment with 5A peptide potently restricted DSS-induced inflammation, as indicated by improved disease activity indices and colon histology, as well as decreased intestinal tissue myeloperoxidase levels and plasma TNF? and IL-6 concentrations. Additionally, plasma levels of monocyte chemoattractant protein-1 and the monocyte expression of adhesion-mediating molecule CD11b were down-regulated, pro-inflammatory CD11b(+) /Ly6c(high) monocytes were decreased, and the number of intestinal monocytes was reduced in 5A peptide-treated animals as determined by intravital macrophage-related peptide-8/14-directed fluorescence-mediated tomography and post-mortem immunhistochemical F4/80 staining. Intravital fluorescence microscopy of colonic microvasculature demonstrated inhibitory effects of 5A peptide on leukocyte adhesion accompanied by reduced plasma levels of the soluble adhesion molecule sICAM-1. In vitro 5A peptide reduced monocyte adhesion and transmigration in TNF?-stimulated monolayers of human intestinal microvascular endothelial cells. Increased susceptibility to DSS-induced inflammation was noted in apoA-I(-/-) mice.Conclusions and implicationsThe 5A peptide is effective at ameliorating murine colitis by preventing intestinal monocyte infiltration and activation. These findings point to apoA-I mimetics as a potential treatment approach for IBD.
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Project description:Colorectal cancer (CRC) is often diagnosed at an advanced stage when tumor cell dissemination has taken place. Chemo- and targeted therapies provide only a limited increase of overall survival for these patients. The major reason for clinical outcome finds its origin in therapy resistance. Escape mechanisms to both chemo- and targeted therapy remain the main culprits. Here, we evaluate major resistant mechanisms and elaborate on potential new therapies. Amongst promising therapies is ?-amanitin antibody-drug conjugate targeting hemizygous p53 loss. It becomes clear that a dynamic interaction with the tumor microenvironment exists and that this dictates therapeutic outcome. In addition, CRC displays a limited response to checkpoint inhibitors, as only a minority of patients with microsatellite instable high tumors is susceptible. In this review, we highlight new developments with clinical potentials to augment responses to checkpoint inhibitors.
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