Adaptive immune cells within ectopic lymphoid-like structures are nurturing hepatocellular carcinoma cells

Lymph nodes represent secondary lymphoid tissues. They are designed to facilitate detection and initiation of adaptive immune response to foreign antigens. There are, however, tertiary lymphoid-like structures, also called ectopic [out-of-place] lymphoid-like structures, that are usually associated with chronic inflammation or tumors. 

Generally, scientists assumed that ectopic lymphoid-like structures provided additional help to control tumors or chronic inflammation. However, paradoxically, new study in journal Nature Immunology provided evidence that ectopic lymphoid-like structures associated with liver tumor, hepatocellular carcinoma, were actively supporting progenitor cancer cell growth and tumor expansion.

First the authors found that presence of ectopic lymphoid-like structures [and its signature] were negatively correlated with survival in hepatocellular carcinoma (HCC) patients.

Next, the authors have used genetically modified mice expressing liver-specific constitutively active NF-κB [to drive inflammation]. Starting at 7 months of age, these mice, IKKβ(EE)^Hep, developed ectopic lympoid-like structures (ELS) in the liver.

Interestingly, IKKβ(EE)^Hep mice on RAG KO background, that lack adaptive T and B cells and ectopic lymphoid-like structures (ELS), showed resistance for HCC development when exposed to carcinogen diethylnitrosamine (DEN). 

Similar effect on HCC tumor burden were seen in diethylnitrosamine treated IKKβ(EE)^Hep mice exposed to anti-Thy-1.2 antibody injection [that depletes T cells and some NKT cells].

Finally, the authors showed that in IKKβ(EE)^Hep mice early application of antibody directed to lymphotoxin-β receptor (LTβR-Ig) signaling could prevent HCC "addiction" to stimulating immune cytokines (LTβ and LTα or LIGHT).

In summary, this study indicates that chronic liver inflammation (in response to genotoxic reagents or viral infection) promotes tertiary lymphoid tissue development that in turn could harbor and nurture early cancer progenitors by providing immune cytokines such as LTβ and LTα or LIGHT.

This observation is in contrast to the role of ectopic lymphoid-like structures play in several other tumors (colon, mammary, breast, skin). These data would require rethinking of how immunotherapy could be applied for HCC treatment.

David Usharauli

TNF-α sensing by brain is required for early mobilization of adaptive immune system

Very few studies have been done with the focus on understanding the relationship between brain and adaptive immune system. In principle, rapid sensing of peripheral insults by neurons and information analysis by brain could facilitate efficient recruitment of adaptive immune cells.

For example, new study in journal Nature Immunology provided evidence to suggest that infection-associated TNF-α signals brain (hypothalamus) to induce rapid lypolysis in adipose tissue and recruitment of adaptive immune cells.

Initially, the authors showed that direct injection of 10pg of TNF-α into mouse hypothalamus induced rapid mobilization of T and B cells in the spleen and adipose tissue (similar effect was seen with an intravenous L.M infection). 

Next, the authors showed that such mobilization of adaptive immune cells during an intravenous L.M infection was reduced when TNF-α antagonist was injected into hypothalamus. 

Similarly, such mobilization of adaptive immune cells in the spleen and adipose tissue during an intravenous L.M infection was reduced when TNF-α signaling was inhibited in hypothalamus by shRNA.

Conversely, when TNF-R deficient mice were injected in the hypothalamus with lentivirus construct encoding TNFR1, mobilization of adaptive immune cells in the spleen and adipose tissue was restored during an intravenous L.M infection.

Furthermore, sympathetic denervation of adipose tissue also abolished mobilization of adaptive immune cells in the spleen and adipose tissue in response to hypothalamic TNF-α injection.

Next, the authors showed that mobilization of adaptive immune cells in the spleen and adipose tissue in response to an intravenous L.M infection or hypothalamic TNF-α injection was reversed by lypolysis inhibitor, implying that brain signaled the adaptive immune system via lipid metabolites.

Finally, the authors made observation that diet-induced obesity rendered mice insensitive to hypothalamic injection of TNF-α, provided indirect evidence of diminished immune activity in obesity.

In summary, these results points to a novel inter-talk mechanism, based on lypolysis products, between brain and adaptive immune system at an early stage of infection. Right now it is not clear whether this brain-assisted rapid mobilization of adaptive immune cells could translate into efficient immune response against infection later on. 

David Usharauli