Liver Immune Microenvironment and Metastasis from Colorectal Cancer-Pathogenesis and Therapeutic Perspectives

SIMPLE SUMMARY: Liver metastasis remains the major contributor in colorectal cancer-related death. It has become clear that the unique immune features of liver microenvironment take part in many steps of metastatic cascade, from pre-metastatic niche formation, tumor cell colonization to metastatic tumor establishment. Therefore, better understanding of mechanisms orchestrating the formation of a hospitable hepatic metastatic niche is necessary for the development of effective therapies. This review summarizes the current understandings of the critical role of liver immune microenvironment in metastasis development and provides therapeutic perspective on targeting the metastasis-prone microenvironment. ABSTRACT: A drastic difference exists between the 5-year survival rates of colorectal cancer patients with localized cancer and distal organ metastasis. The liver is the most favorable organ for cancer metastases from the colorectum. Beyond the liver-colon anatomic relationship, emerging evidence highlights the impact of liver immune microenvironment on colorectal liver metastasis. Prior to cancer cell dissemination, hepatocytes secrete multiple factors to recruit or activate immune cells and stromal cells in the liver to form a favorable premetastatic niche. The liver-resident cells including Kupffer cells, hepatic stellate cells, and liver-sinusoidal endothelial cells are co-opted by the recruited cells, such as myeloid-derived suppressor cells and tumor-associated macrophages, to establish an immunosuppressive liver microenvironment suitable for tumor cell colonization and outgrowth. Current treatments including radical surgery, systemic therapy, and localized therapy have only achieved good clinical outcomes in a minority of colorectal cancer patients with liver metastasis, which is further hampered by high recurrence rate. Better understanding of the mechanisms governing the metastasis-prone liver immune microenvironment should open new immuno-oncology avenues for liver metastasis intervention.