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β-Catenin inhibition shapes tumor immunity and synergizes with immunotherapy in colorectal cancer.

ABSTRACT: In colorectal cancer, Wnt/β-catenin signaling is often aberrantly activated and associated with a T-cell-excluded phenotype which is a major obstacle for many immunotherapies. However, the effects of Wnt/β-catenin inhibition on tumor immunity and immunotherapy remain to be elucidated. In syngeneic mouse models of colorectal cancer, β-catenin/TCF inhibitor iCRT14 potently enhanced the infiltration of T and NK cells, without influencing their proliferation or the infiltration of most myeloid populations. Mechanistically, β-catenin inhibition upregulated while its overexpression suppressed the expression of T/NK cell-recruiting CXCR3 chemokines CXCL9/10/11 in both mouse and human colorectal cancer cells. Furthermore, iCRT14 treatment synergized with tumor vaccines or Treg cell ablation to achieve a complete inhibition of tumor growth in syngeneic models of CT26-OVA and MC38-S33Y.β-cat, respectively. Taken together, our work reveals that β-catenin inhibition shifts colorectal tumor microenvironment into a T-cell-inflamed phenotype and potentiates the efficacy of other immunotherapeutic strategies for colorectal cancer.

SUBMITTER: Wang C

PROVIDER: S-EPMC7470182 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Wnt/beta-catenin signaling in T-cell immunity and cancer immunotherapy.

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Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

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SEMA4D Knockdown Attenuates <i>β</i>-Catenin-Dependent Tumor Progression in Colorectal Cancer.

Project description:Semaphorin 4D (SEMA4D), a protein originally demonstrated to regulate the immune system and axonal growth cone collapse in the developing central nervous system, is overexpressed in various human malignancies, including colorectal cancer (CRC). This investigation was undertaken to examine the effects of SEMA4D silencing on the biological properties of the CRC cell line. SW48 cells were transfected with a siRNA-targeting SEMA4D. The mRNA expression of underlying pro- and antiapoptotic proteins including Bax, Bcl-2, P53, and caspase-3, cancer stem cell (CSC) markers, epithelial-mesenchymal transition (EMT) markers, MMP-2, and MMP-9 was examined using qRT-PCR. Further, the protein expression of E-cadherin and β-catenin was confirmed by Western blot. SW48 cell migration and MMP activity were detected using scratch and zymography analysis, respectively. Finally, the apoptosis rate was assessed via the flowcytometry test. SEMA4D knock-down was associated with a considerable suppression of in vitro cell viability, EMT-related genes, CSC markers, β-catenin signaling pathway, sphere-forming, cell migration, and MMP-2 activity as well as induction of apoptosis. This study identifies the inhibitory effects of SEMA4D gene silencing on tumor progression. Thereby, this might conclude a possible alternative to cancer therapy by targeting several prominent pathways involved in cancer through SEMA4D suppression.

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