Immune microenvironment of hepatocellular carcinoma, intrahepatic cholangiocarcinoma and liver metastasis of colorectal adenocarcinoma: Relationship with histopathological and molecular classifications

Abstract

Tumor tissue is composed of tumor cells and tumor stroma. Tumor stroma contains various immune cells and non-immune stromal cells, forming a complex tumor microenvironment which plays pivotal roles in regulating tumor growth. Recent successes in immunotherapies against tumors, including immune checkpoint inhibitors, have further raised interests in the immune microenvironment of liver carcinoma. The immune microenvironment of tumors is formed because of interactions among tumor cells, immune cells and non-immune stromal cells, including fibroblasts and endothelial cells. Different patterns of immune microenvironment are observed among different tumor subtypes, and their clinicopathological significance and intertumor/intratumor heterogeneity are being intensively studied. Here, we review the immune microenvironment of hepatocellular carcinoma, intrahepatic cholangiocarcinoma and liver metastasis of colorectal adenocarcinoma, focusing on its histopathological appearance, clinicopathological significance, and relationship with histological and molecular classifications. Understanding the comprehensive histopathological picture of a tumor immune microenvironment, in addition to molecular and genetic approaches, will further potentiate the effort for precision medicine in the era of tumor-targeting immunotherapy.

Immune microenvironment in primary and metastatic liver cancers

“…We read with great interest the review article titled "Immune microenvironment of hepatocellular carcinoma, intrahepatic cholangiocarcinoma and liver metastasis of colorectal adenocarcinoma: Relationship with histopathological and molecular classifications," by Kurebayashi et al 1 recently published in Hepatology Research. The authors reviewed the tumor immune microenvironment (TIME) of hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (iCCA), and liver metastasis of colorectal adenocarcinoma (LM-CRC).…”

“…Sun et al 7 found that high intratumoral infiltration with CD8 + T cells was the best predictor of a favorable survival effect of classifications for CD3 and CD8 cells within the tumor and at the surgical margin. Furthermore, Kurebayashi et al 1 review evidence showing frequent infiltration of the tumor margin with CD8 + T cells that prevents direct exposure of tumor cells to nontumor liver tissue. It is therefore important to clarify the underlying mechanism as well as the function of CD8 + T cells that infiltrate the tumor.…”

“…Kurebayashi et al 1 and Job et al 10 focus on mesenchymal iCCA and categorize four subtypes of iCCA. They note that a pattern of infiltrating T and B cells is a hallmark of a reactive immune environment associated with better prognosis of patients with iCCA.…”

The Tumor Microenvironment in Liver Metastases from Colorectal Carcinoma in the Context of the Histologic Growth Patterns

“…Conversely, in the "replacement" subtype, there is a direct contact between hepatocytes and tumoral cells. In "replacement" HGP, also called "invasive", tumor cells infiltrate liver parenchyma, replacing the hepatocytes and following the hepatic sinusoidal structure, which makes it difficult to clearly distinguish the tumor border [15]. Finally, in the "pushing" or "expansive" HGP, tumoral cells literally "push" the hepatocytes, which become flattened in consequence, and the tumor border is clearly demarcated, but no fibrotic tissue intervenes.…”

<p>Emerging Role of Immunotherapy for Colorectal Cancer with Liver Metastasis</p>

“…117 Furthermore, lymphocyte infiltration and plasma cell infiltration are linked to prolonged patient survival in CLM. 118,119 Several key factors contribute to the extravasation of CRC cells into the liver. 120 First, the blood circulation system in the liver is complicated and enriched.…”