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Liver metastasis from colorectal cancer: pathogenetic development, immune landscape of the tumour microenvironment and therapeutic approaches.

ABSTRACT: Colorectal cancer liver metastasis (CRLM) is one of the leading causes of death among patients with colorectal cancer (CRC). Although immunotherapy has demonstrated encouraging outcomes in CRC, its benefits are minimal in CRLM. The complex immune landscape of the hepatic tumour microenvironment is essential for the development of a premetastatic niche and for the colonisation and metastasis of CRC cells; thus, an in-depth understanding of these mechanisms can provide effective immunotherapeutic targets for CRLM. This review summarises recent studies on the immune landscape of the tumour microenvironment of CRLM and highlights therapeutic prospects for targeting the suppressive immune microenvironment of CRLM.

SUBMITTER: Wang Y

PROVIDER: S-EPMC10362774 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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Liver metastasis from colorectal cancer: pathogenetic development, immune landscape of the tumour microenvironment and therapeutic approaches.

Wang Yaxian Y Zhong Xinyang X He Xuefeng X Hu Zijuan Z Huang Huixia H Chen Jiayu J Chen Keji K Zhao Senlin S Wei Ping P Li Dawei D

Journal of experimental & clinical cancer research : CR 20230722 1

Colorectal cancer liver metastasis (CRLM) is one of the leading causes of death among patients with colorectal cancer (CRC). Although immunotherapy has demonstrated encouraging outcomes in CRC, its benefits are minimal in CRLM. The complex immune landscape of the hepatic tumour microenvironment is essential for the development of a premetastatic niche and for the colonisation and metastasis of CRC cells; thus, an in-depth understanding of these mechanisms can provide effective immunotherapeutic ...[more]

PMID: 37480104

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Project description:Background: Colorectal cancer, the fourth leading cause of cancer mortality, is prone to metastasis, especially to the liver. The pre-metastatic microenvironment comprising various resident stromal cells and immune cells is essential for metastasis. However, how the dynamic evolution of immune components facilitates pre-metastatic niche formation remains unclear. Methods: Utilizing RNA-seq data from our orthotopic colorectal cancer mouse model, we applied single sample gene set enrichment analysis and Cell type Identification By Estimating Relative Subsets Of RNA Transcripts to investigate the tumor microenvironment landscape of pre-metastatic liver, and define the exact role of myeloid-derived suppressor cells (MDSCs) acting in the regulation of infiltrating immune cells and gene pathways activation. Flow cytometry analysis was conducted to quantify the MDSCs levels in human and mice samples. Results: In the current work, based on the high-throughput transcriptome data, we depicted the immune cell infiltration pattern of pre-metastatic liver and highlighted MDSCs as the dominant altered cell type. Notably, flow cytometry analysis showed that high frequencies of MDSCs, was detected in the pre-metastatic liver of orthotopic colorectal cancer tumor-bearing mice, and in the peripheral blood of patients with stage I-III colorectal cancer. MDSCs accumulation in the liver drove immunosuppressive factors secretion and immune checkpoint score upregulation, consequently shaping the pre-metastatic niche with sustained immune suppression. Metabolic reprogramming such as upregulated glycolysis/gluconeogenesis and HIF-1 signaling pathways in the primary tumor was also demonstrated to correlate with MDSCs infiltration in the pre-metastatic liver. Some chemokines were identified as a potential mechanism for MDSCs recruitment. Conclusion: Collectively, our study elucidates the alterations of MDSCs during pre-metastatic niche transformation, and illuminates the latent biological mechanism by which primary tumors impact MDSC aggregation in the targeted liver.

Project description:BackgroundLiver metastasis is the leading cause of death in colorectal cancer (CRC) patients, and the precise mechanisms remain unclear. In this study, single-cell RNA sequencing (scRNA-seq) was used to analyze the cellular and molecular heterogeneity between CRC primary lesion and corresponding liver metastasis, and to clarify the characteristics of the tumor microenvironment (TME) in synchronous liver metastasis of CRC.MethodsA case of microsatellite stable (MSS) sigmoid carcinoma with synchronous liver metastasis was selected, and tissues from the primary tumor and the liver metastasis were collected for scRNA-seq. The EdgeR package software was used to identify the differentially expressed genes between cells. Gene Set Enrichment Analysis (GSEA) was performed and the clusterProfiler R package was used for Gene Ontology (GO) enrichment analysis. The SCENIC and CellphoneDB packages were used to reconstruct the transcriptional regulatory networks and to analyze the intercellular interaction network, respectively.ResultsCompared to the primary tumor, the proportion of myeloid cells in the metastatic tumor was significantly increased, while B cells and plasma cells were decreased. In the metastatic tumor, the myeloid-derived suppressor cell (MDSC) characteristic gene, mannose receptor C-type 1 (MRC1) and tumor associated macrophage 2 (TAM2)-related gene, were highly expressed. Furthermore, angiogenesis, oxidative phosphorylation, and endothelial mesenchymal transition (EMT) of myeloid cells were also significantly enhanced. There were less myeloid cells in primary tumors, and these were mainly monocytes and TAM1; while the number of TAM2 was significantly upregulated in the metastatic samples. In liver metastasis, the T cell population was exhausted, and this was accompanied by a significant increase in the number of CD4+ T cells and a decrease in the number of CD8+ T cells. Furthermore, some immune checkpoint molecules were highly expressed. Interactions between myeloid cells and other cell populations appeared to be strong.ConclusionsThe TME of CRC liver metastasis is significantly immunosuppressed. Interactions between myeloid cells and other cell populations in the TME contribute to the establishment of a pro-metastatic niche that promotes colonization and growth of CRC cells in the liver. TAMs may be a potential immunotherapeutic target for MSS CRC.

Project description:BackgroundLiver metastasis is common in colorectal cancer patients. Immunotherapy covers a wide range of tumor types and is safer than traditional radiotherapy and chemotherapy. However, its overall effective rate is only 20-40%. At present, there is a lack of relevant research clarifying whether the changes and clinical significance of the immune microenvironment in colorectal cancer patients with liver metastasis are conducive to enhancing the promotion and further improving the efficacy of immunotherapy.MethodsWe retrospectively collected the data of 50 colorectal cancer patients with liver metastasis treated in Chongqing University Cancer Hospital from January 2017 to January 2019. Liver metastatic cancer tissues and normal liver tissues were collected to detect the levels of immune cells in the two samples. At the same time, the correlation between T-cell subsets in the liver metastatic cancer tissue immune microenvironments of colorectal cancer patients and prognosis was analyzed.ResultsCompared with the normal liver tissues, the level of T helper cell 1/T helper cell 2 (Th1/Th2) in the liver metastatic cancer tissues was significantly decreased (0.88±0.24 vs. 1.34±0.27, P=0.000), while the levels of regulatory T cells were markedly increased (8.57±2.31 vs. 6.89±1.71, P=0.000). The Th1/Th2 level in liver metastatic cancer tissue exhibited a good predictive value for recurrence and survival 3 years after surgery, and the areas under the curves were 0.783 (95% confidence interval: 0.649-0.916, P=0.002) and 0.763 (95% confidence interval: 0.628-0.898, P=0.001), respectively. Moreover, the regulatory T-cell level in liver metastatic cancer tissue had a good predictive value for recurrence and survival at 3 years postoperatively, and the areas under the curves were 0.788 (95% confidence interval: 0.656-0.919, P=0.002) and 0.763 (95% confidence interval: 0.628-0.897, P=0.001), respectively.ConclusionsThe immunosuppressive condition of liver metastasis in colorectal cancer patients was related to poor prognosis.

Dataset Information

Liver metastasis from colorectal cancer: pathogenetic development, immune landscape of the tumour microenvironment and therapeutic approaches.

Publications

Liver metastasis from colorectal cancer: pathogenetic development, immune landscape of the tumour microenvironment and therapeutic approaches.

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