Chronic inflammation, immune escape, and oncogenesis in the liver: a unique neighborhood for novel intersections

Abstract

Sustained hepatic inflammation, driven by alcohol consumption, nonalcoholic fatty liver disease, and/or chronic viral hepatitis (hepatitis B and C), results in damage to parenchyma, oxidative stress, and compensatory regeneration/proliferation. There is substantial evidence linking these inflammation-associated events with the increased incidence of hepatocellular carcinogenesis. Although acute liver inflammation can play a vital and beneficial role in response to liver damage or acute infection, the effects of chronic liver inflammation, including liver fibrosis and cirrhosis, are sufficient in a fraction of individuals to initiate the process of transformation and the development of hepatocellular carcinoma. This review highlights immune-dependent mechanisms that may be associated with hepatocellular oncogenesis, including critical transformative events/pathways in the context of chronic inflammation and subverted tolerogenesis.

Figure 1. Avoiding hepatocellular oncogenesis through immune-mediated processes

Failsafe mechanisms to counter malignant transformation of hepatocytes involve both cell intrinsic and extrinsic components. In response to cellular damage, cell intrinsic checkpoint pathways arrest cell growth (senescence, autophagy) and/or initiate programs that result in clearance (apoptosis). In the liver, these programs elicit specific extrinsic responses by local immune cells. During the progression to hepatocellular transformation, oncogene activation can also induce both apoptosis and senescence. Both processes result in release of cytokines and chemokines (SASP, senescence associated secretory phenotype and DAMPS, damage associated molecular patterns) into the microenvironment to recruit and instruct immune system cells to reinforce these processes. Innate immune components such as NK and KC stand watch for signs of oncogene-induced hepatocellular stress such as NKG2D and DAMPS (IL-1α, HMGb1). KC also serve as the primary source for IL-6 in the orchestration of compensatory proliferation required for both hepatic regeneration and tumor progression. CD4⁺ adaptive immune responses are mounted against oncogene induced senescent cells leading to clearance effected by macrophages. Oncogene-initiated cells may escape these mechanisms by acquiring additional or “2^nd hits” in these pathways leading to transformation.

Figure 2. Malignant repurposing of immune surveillance and tolerance in HCC

Prolonged hepatitis induces alterations in TGF-β, IL-10, IL-13, and IL-4 and leads to an immune milieu permissive for hepatocellular transformation. IL-10, produced by MDSC, KC, B and Treg cells, downregulates the anti-tumor effect of NK, CTL, Th1 and DC cells. KC and HSC activation leads to elevated TGF-β levels stimulating Tregs and inhibiting CTLs. IL-13 and IL-4 produced by Th2 further inhibit Th1 cells MDSCs inhibit NK and CTL activity through NKp30 and PD-1. The concerted effect of these activities results in reduced immune sensitivity and increased tolerance.