The induction of antitumor immunity by vaccines or immunotherapies is inhibited by the immunosuppressive microenvironment of tumors. Toll-like receptor (TLR) agonists have the potential to increase inflammatory antitumor effects in the microenvironment, but these ligands can exert a mixture of both positive and negative effects on inflammation.
Tumor Growth and Survival
Marshall and colleagues from Trinity College Dublin, Ireland, and Bioceros, Utrecht, The Netherlands, recently showed that small-molecule inhibitors of phosphoinositide 3-kinase (PI3K) reduce immunosuppression in tumor cells and increase the proinflammatory effects of TLR agonists that support antitumor immunity. In three different mouse models of cancer, the combination of a TLR5 agonist (flagellin) with a class I PI3K inhibitor delayed tumor growth and increased survival, with complete tumor rejection and resistance to secondary challenge being observed in some cases. Tumor growth suppression was associated with accumulation of polyfunctional T cells that produced effector cytokines including interferon (IFN)-α, interleukin (IL)-17, and IL-2. Mice deficient in IL-17 or IFN-α did not exhibit protection from tumor growth.
The authors stated “[O]ur results indicate that PI3K inhibition heightens the antitumor properties of TLR ligands, eliciting tumor regression directly but also indirectly by relieving suppressive signals that restrict potent antitumor T-cell responses. These findings suggest important uses for PI3K inhibitors in heightening responses to cancer immunotherapy and immunochemotherapy.” ■
Marshall NA, et al: Cancer Res 72:581-591, 2012.