SUMMARY Here, we report that kinase-dead IKKα knock-in mice develop spontaneous lung squamous cell carcinomas (SCCs) associated with IKKα downregulation and marked pulmonary inflammation. IKKα reduction upregulated the expression of p63, Trim29, and keratin 5 (K5), which serve as diagnostic markers for human lung SCCs. IKKαlowK5+p63hi cell expansion and SCC formation were accompanied by inflammation-associated deregulation of oncogenes, tumor suppressors, and stem cell regulators. Reintroducing transgenic K5.IKKα, depleting macrophages, and reconstituting irradiated mutant animals with WT bone marrow (BM) prevented SCC development, suggesting that BM-derived IKKα-mutant macrophages promote the transition of IKKαlowK5+p63hi cells to tumor cells. This mouse model resembles human lung SCCs, sheds light on the mechanisms underlying lung malignancy development, and identifies targets for therapy of lung SCCs.

Sustained hepatic inflammation, driven by factors such as alcohol consumption, non-alcoholic fatty liver disease (NAFLD) 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. While 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 (HCC). 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.

Mammalian target of rapamycin (mTOR) is a central mediator of cancer cell growth, but it also directs immune cell differentiation and function. On this basis, we have explored the hypothesis that mTOR inhibition can enhance cancer immunotherapy. Here we report that a combination of αCD40 agonistic antibody and the ATP-competitive mTOR kinase inhibitory drug AZD8055 elicited synergistic anti-tumor responses in a model of metastatic renal cell carcinoma. In contrast to the well-established mTOR inhibitor rapamycin, AZD8055 increased the infiltration, activation and proliferation of CD8+ T cells and NK cells in liver metastatic foci when combined with the CD40 agonist. AZD8055/ αCD40-treated mice also display an increased incidence of matured macrophages and dendritic cells compared to that achieved in mice by αCD40 or AZD8055 treatment alone. We found that the combination treatment also increased macrophage production of TNFα; which played an indispensable role in activation of the observed anti-tumor immune response. Levels of Th1 cytokines, including IL-12, IFN-γ, TNFα, and the Th1-associated chemokines RANTES, MIG and IP-10 were each elevated significantly in the livers of mice treated with the combinatorial therapy versus individual treatments. Notably, the AZD8055/αCD40-induced anti-tumor response was abolished in IFN-γ −/− and CD40 −/− mice, establishing the reliance of the combination therapy on host IFN-γ and CD40 expression. Our findings offer a preclinical proof of concept that, unlike rapamycin, the ATP-competitive mTOR kinase inhibitor AZD8055 can contribute with αCD40 treatment to trigger a restructuring of the tumor immune microenvironment to trigger regressions of an established metastatic cancer.