Wednesday, October 28, 2015

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

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