MGP promotes CD8⁺ T cell exhaustion by activating the NF-κB pathway leading to liver metastasis of colorectal cancer

Abstract

Matrix Gla protein (MGP) was originally reported as a physiological suppressor of ectopia calcification and has also been reported to be associated with cancer. However, the relation between the biological functions of MGP and the immune response in colorectal cancer (CRC) remains unclear. Here, we investigated the regulatory role of MGP in the immune microenvironment of CRC. MGP expression in CRC samples was assessed by single-cell RNA sequencing and the Gene Expression Omnibus (GEO) database, and confirmed by quantitative real-time Polymerase Chain Reaction (qRT-PCR) and immunohistochemistry analysis of human CRC samples. The effect of MGP on proliferation and invasion of CRC cells was evaluated by in vitro assays involving MGP knockdown and overexpression. Luciferase reporter assay and chromatin immunoprecipitation (ChIP)-qPCR assay were performed to identify transcriptional regulatory sites of the nuclear factor kappa-B (NF-κB) and programmed cell death ligand 1 (PD-L1). In vivo experiments were performed in mouse model of CRC liver metastasis established via spleen injection. The results revealed that MGP was significantly upregulated in cancer cell clusters from the primary CRC or liver metastases, compared with that in the corresponding paracancerous tissues via single-cell RNA sequencing. MGP enriched intracellular free Ca 2+ levels and promoted NF-κB phosphorylation, thereby activated PD-L1 expression to promote CD8 + T cell exhaustion in CRC. The luciferase reporter assay and ChIP-qPCR assay indicated that the transcriptional regulation of NF-κB upregulated PD-L1 expression. In vivo , MGP inhibition significantly decreased the rate of CRC liver metastasis, which was further reduced after combined therapy with αPD1 (anti-PD1). In conclusions, this study revealed that MGP can facilitate CD8 + T cell exhaustion by activating the NF-κB pathway, leading to liver metastasis of CRC. The combination of MGP knockdown and αPD1 can synergistically resist liver metastasis of CRC.

Establishment and validation of exhausted CD8+ T cell feature as a prognostic model of HCC

“…These transcription factors include: ILF3, RFXANK, RFXAP, RFX5, CIITA, RELA, NFKB1, AR, E2F1, STAT3 and JUN. Consistent with the conclusions of other studies, NFKB1/RelA heterodimers participated in NF-κB signaling pathway activation, which is an important factor for Tex production ( 35 – 37 ). Transcription factors CIITA, RFX5, RFXAP, and RFXANK mutations have been associated with Major histocompatibility complex (MHC) II deficiency, so they’re also associated with immune exhaustion.…”

Upregulation of APOC1 Promotes Colorectal Cancer Progression and Serves as a Potential Therapeutic Target Based on Bioinformatics Analysis

“…TAMs had much higher levels of APOC1 than other cell clusters such as CD8 T, CD4 T, and NK cells, which were both less expressed (Figure 5(b)). Furthermore, we looked at the data from Hae-Ock Lee et al [18] and discovered that APOC1 was primarily expressed in myeloid CRC tissues (Figures 6(a) and 6(b)), which is similar to our fndings. Our intense curiosity about the function of APOC1 in TAMs from CRC was piqued by all of these analyses.…”

Landscapes and mechanisms of CD8+ T cell exhaustion in gastrointestinal cancer

“…Thus, clearing tumor-associated ammonia reboots T cells and improves anti-PD-L1 efficacy ( 133 ). Elevated in CRC cancer cells, Matrix Gla protein (MGP) increases intracellular free Ca 2+ levels, promotes NF-κB phosphorylation, and activates PD-L1 expression, leading to CD8 + TEX ( 134 ). PTPN2 mediates the generation of the Tim-3 subpopulation, and loss of Ptpn2 promotes the differentiation and formation of the Tim-3 + CD8 + T cells and increases Tim-3 + CD8 + T cell responses in MC38 cancer models ( 135 ).…”