Immunotherapy with PI3K Inhibitor and Toll-Like Receptor Agonist Induces IFN-γ+IL-17+ Polyfunctional T Cells That Mediate Rejection of Murine Tumors

Abstract

The immunosuppressive microenvironment in tumors hampers the induction of antitumor immunity by vaccines or immunotherapies. Toll-like receptor (TLR) ligands have the potential to treat tumors, but they can exert a mixture of positive and negative effects on inflammation in the tumor microenvironment. In this study, we show that specific small molecule inhibitors of phosphoinositide 3-kinase (PI3K) relieve immunosuppression to heighten the proinflammatory effects of TLR ligands that support antitumor immunity. Multiple strategies to inhibit PI3K in dendritic cells (DC) each led to suppression of interleukin (IL)-10 and TGF-b but did affect IL-12 or IL-1b induction by the TLR5 ligand flagellin. In three different mouse models of cancer, combining flagellin with a class I PI3K inhibitor, either with or without a DC vaccine, delayed tumor growth and increased survival, with some animals exhibiting complete rejection and resistance to secondary challenge. Tumor growth suppression was associated with increased accumulation of polyfunctional T cells that secreted multiple effector cytokines, including IFN-g, IL-17, and IL-2. Therapeutic protection was abolished in mice deficient in IL-17 or deprived of IFN-g. Together, our results indicate that PI3K inhibition heighten 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. Cancer Res; 72(3); 581-91. Ó2011 AACR.

Twelve-year survival and immune correlates in dendritic cell–vaccinated melanoma patients

“…In our current trial, we have confirmed our previous data, implicating that vaccinespecific CD8 + T cells expanded by the current DC type are IFNγ-producing and lytic (24,33,56,57), cover a wide spectrum of TCR affinities including high-affinity CD8 + T cells capable of killing HLAmatched or autologous melanoma lines, and remain as memory T cells even at prolonged vaccination intervals. We now also demonstrated in accordance with recent reports (58) that the vaccine-specific CD8 + T cells were polyfunctional, a property considered relevant for antiviral (59)(60)(61) and antitumor efficacy (62)(63)(64).…”

The PI3K Pathway in Human Disease

“…In murine DCs stimulated with flagellin in the presence of killed tumor cells, PI3K inhibitors suppressed production of IL-10 and TGFβ while preserving or enhancing IL-12 release (Marshall et al, 2012). In a tumor vaccine model, adoptive transfer of PI3K inhibitor-treated DCs enhanced anti-tumor efficacy and fostered the expansion of effector T cells secreting inflammatory cytokines IFNγ and IL-17 (Marshall et al, 2012). This type of approach holds promise for improving efficacy of DC-based vaccines while avoiding systemic administration of PI3K-mTOR pathway inhibitors.…”

The New Era of Cancer Immunotherapy

“…Interestingly, the combination of the inhibitor with the E7 vaccine was able to enhance the vaccine induced immune control in a TC-1 tumor model, showing that the combined strategy of PI3K inhibition with other immunotherapeutic approaches may act synergistically. Along these lines, synergistic antitumor activity has been observed by combining a class I PI3K inhibitor and the TLR5 ligand flagellin (Marshall et al, 2012).…”