Tumor microenvironment in primary liver tumors: A challenging role of natural killer cells

Abstract

In the last years, several studies have been focused on elucidate the role of tumor microenvironment (TME) in cancer development and progression. Within TME, cells from adaptive and innate immune system are one of the main abundant components. The dynamic interactions between immune and cancer cells lead to the activation of complex molecular mechanisms that sustain tumor growth. This important cross-talk has been elucidate for several kind of tumors and occurs also in patients with liver cancer, such as hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA). Liver is well-known to be an important immunological organ with unique microenvironment. Here, in normal conditions, the rich immune-infiltrating cells cooperate with non-parenchymal cells, such as liver sinusoidal endothelial cells and Kupffer cells, favoring self-tolerance against gut antigens. The presence of underling liver immunosuppressive microenvironment highlights the importance to dissect the interaction between HCC and iCCA cells with immune infiltrating cells, in order to understand how this cross-talk promotes tumor growth. Deeper attention is, in fact, focused on immune-based therapy for these tumors, as promising approach to counteract the intrinsic anti-tumor activity of this microenvironment. In this review, we will examine the key pathways underlying TME cell-cell communications, with deeper focus on the role of natural killer cells in primary liver tumors, such as HCC and iCCA, as new opportunities for immune-based therapeutic strategies.

Keywords: Hepatocellular carcinoma; Immune cells; Intrahepatic cholangiocarcinoma; Natural killer cells; Primary liver cancer; Tumor microenvironment.

Figure 1

Representative image of the main cellular component of tumor microenvironment. Tumors present a wide array of cells from both innate and adaptative immunity (i.e., macrophages, natural killer cells, neutrophils and lymphocytes) able to foster cancer growth and malignancy.

Figure 2

Mechanisms involved in hepatocellular carcinoma immune evasion. In physiological conditions, liver has the ability to induce immunotolerance against antigen from gastrointestinal tract. These mechanisms have a detrimental role during hepatocellular carcinoma development and progression. Upregulation of inhibitory programmed death-ligand 1 molecule from tumor cells, Kupffer cells, liver sinusoidal endothelial cells and antigen presenting cells, together with the release of interleukin-10 and transforming growth factor beta, lead to an exhausted phenotype of CD8+ cells and prevent tumor cells from immune damage. HCC: Hepatocellular carcinoma; PD-L1: Programmed death-ligand 1; CTL4A: Cytotoxic T lymphocyte antigen 4; PD-1: Programmed cell death protein 1; TGFβ: Transforming growth factor beta; IL-10: Interleukin-10.

Figure 3

Modulation of natural killer cells cytotoxic activity in hepatocellular carcinoma. Tumor cells with tumor-associated macrophages and other cells within tumor microenvironment are involved in dysfunctional activity of natural killer cells (NK), reducing their ability to recognize and eliminate malignant cells. Down regulation of NKG2D, up-regulation of different inhibitory receptors, secretion of cytokines from cancer-associated fibroblasts and Treg, interaction of CD48/2B4 are the main mechanisms involved in NK exhaustion. HCC: Hepatocellular carcinoma; NK: Natural killer cells; CAF: Cancer-associated fibroblasts; TAM: Tumor-associated macrophages; IL-10: Interleukin-10; MHC-1: major histocompatibility complex class I; KIR: Killer Ig-like receptors.

Figure 4

Role of cancer-associated fibroblasts in cholangiocarcinoma. In the figure is shown the paracrine loop between tumor cells and cancer-associated fibroblasts, the main cellular component of cholangiocarcinoma tumor microenvironment (TME). Several survival and recruitment signals are exchanged within TME, leading to tumor growth and progression. CCA: Cholangiocarcinoma; TGFβ: Transforming growth factor beta; PDGF-β: Platelet-derived growth factor receptor beta; EGFR: Endothelial growth factor receptor.