Sirtuin 6 regulates innate immune responses in a syngeneic mouse model of hepatocellular carcinoma

The incidence of most common cancers increases exponentially with advancing age. This occurs coincident to a decline in immune system function, termed immunosenescence suggesting a causal role for cancer development. Epigenetic mechanisms linked to ageing can contribute to cellular ageing and the discovery of ageing genes forms the molecular basis for this relationship. One of these genes is Sirtuin6 (Sirt6), which belongs to the sirtuin family of NAD+-dependent deacetylases. Loss of Sirt6 in mice leads to a severe premature aging-like phenotype leading to an early death of the mice at the age of 4 weeks. Sirt6 is involved in epigenetic gene silencing through histone deacetylation. In our previous work we found a deregulation of differentiation-relevant genes in the livers of Sirt6 deficient mice resulting in an oncofetal phenotype. We could show that this gene signature is predictive for HCC patients with respect to survival and tumor recurrence rates. In recent investigations we have analyzed the immune cell populations present in the bone marrow, blood and spleen and found aging-associated inflammation (inflammaging) like phenotype marked by increased number of myeloid cells in Sirt6-deficient mice. For further studies we have generated a myeloid-specific Sirt6 knockout mouse. Using a syngeneic hepatoma mouse model compatible with the C57BL/6 background we investigated the role of Sirt6 in myeloid derived cells in the antitumor immune responses.