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Macrophage-specific Act1 Knockdown Promoted Adenoma-Adenocarcinoma Transition in Apcmin+/- Mice via Activation of the CXCL9/10-CXCR3 axis

ABSTRACT: macrophages involve in colorectal adenocarcinoma transition. Mouse MC38 colorectal cancer cells were co-cultured with BMDM from both anti-Act1 and Wildtype mice. MC38 cells have higher migration speed and express higher EMT markers including Snail, E-cadherins, and Twist after co-culture with anti-Act1 macrophage. Expression profiling by high throughput sequencing highlighted that by co-culturing with MC38 cells, anti-Act1 macrophage increase proinflammatory cytokines secretion and consequently activates cytokines receptor signaling pathway. Specifically, we identified the mechanism where CXCL9/10 from anti-Act1 macrophage interacted with CXCR3 receptor in MC38 cell to promote MC38 migration as well as EMT. Besides, coculturing with MC38 cells enhanced expressions of PD-L1 and MDSCs markers such as Arg1, iNOS, IDO1 in anti-Act1 macrophages. Among activating pathways, we reveal that anti-Act1 macrophage orchestrates NF-kB and STAT3 signaling pathways to upregulate CXCL9/10 secretion and PD-L1 expression. These findings demonstrate that anti-Act1 in macrophage induced a significant shift in MC38 cells gene expression, and modulating the macrophage-cancer is a viable strategy to assist PD-L1 immunotherapy.

ORGANISM(S): Mus musculus

PROVIDER: GSE183971 | GEO | 2022/09/01

REPOSITORIES: GEO

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Project description:Aim: The aim of this study is to explore the impact of Pien Tze Huang (PZH) on enhancing T cell cytotoxicity by modulating colorectal cancer stem cell (CRC-CSC) markers, programmed death protein ligand-1 (PD-L1), and the transcription factor signal transducer and activator of transcription 3 (STAT3) protein expression in vivo, ex vivo, and in vitro. Methods: HCT116, HCT15, and SW480 cell lines were subjected to treatment with PZH, followed by assessment of cell viability and stemness through CCK8 and spheroid formation assays. Western blot and immunofluorescence techniques were employed to evaluate the expression levels of stem cell markers (DCLK1, CD133, CD44, MET, and LGR5), PD-L1, and STAT3 across three CRC cell lines and five patient-derived organoids (PDOs). Flow cytometry and western blot analyses were utilized to validate T cell expansion from both donors and CRC patients. CRC cells and CRC-PDOs, pre-treated with PZH, were co-cultured with expanded T cells from both donor and autologous peripheral blood mononuclear cells (PBMCs) respectively. The viability of CRC cells and PDOs was evaluated through Calcein-AM staining to measure fluorescence intensity and cell count following co-culture. In the syngeneic MC38 C57BL/6 xenograft model, tumor growth curve and body weight were monitored subsequent to treatment with PZH, anti-PD-1, and PZH combined with anti-PD-1. Immunohistochemistry was performed to assess protein levels of CD133, CD44, STAT3, PD-L1, CD8, and IL-6R in tumor tissue. Results: The effectiveness of PZH in reducing CRC cell viability and suppressing stemness markers, such as LGR5, CD44, MET, DCLK1, and CD133, is evident. PZH also displayed inhibitory effects on tumorigenesis in five CRC-PDOs, with varying sensitivity across cases (3 sensitive and 2 less sensitive). Moreover, PZH enhanced the cytotoxicity of donor T cells against CRC cells and rectified the cytotoxic deficiency or bolstered the cytotoxicity of autologous T cells against CRC-PDOs by downregulating PD-L1 and STAT3 protein expressi Conclusion: PZH enhances T cell-mediated killing effect by inhibiting CRC stem cell markers, PD-L1, and STAT3. Key Words: Pien Tze Huang, patient-derived organoid, colorectal cancer stem cells, programmed death protein ligand-1, signal transducer and activator of transcription 3

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Macrophage-specific Act1 Knockdown Promoted Adenoma-Adenocarcinoma Transition in Apcmin+/- Mice via Activation of the CXCL9/10-CXCR3 axis

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