Inactivation of PI(3)K p110δ breaks regulatory T-cell-mediated immune tolerance to cancer

Abstract

Inhibitors against the p110δ isoform of PI3K have shown remarkable therapeutic efficacy in some human leukaemias1,2. Since p110δ is primarily expressed in leukocytes3, drugs against p110δ have not been considered for the treatment of solid tumours4. We report here that p110δ inactivation in mice protects against a broad range of cancers, including non-haematological solid tumours. We demonstrate that p110δ inactivation in regulatory T cells (Treg) unleashes CD8+ cytotoxic T cells and induces tumour regression. Thus, p110δ inhibitors can break tumour-induced immune tolerance and should be considered for wider use in oncology.

Regulatory T cells in cancer immunotherapy

“…Targeting ZAP-70 may therefore enable selective reduction of TCR signaling by interfering with TCR proximal signaling molecules, resulting in selective death of Treg cells, in particular effector Treg cells, due to signal deprivation-induced apoptosis (Tanaka et al, unpublished). Similarly, an inactivating mutation (D910A mutation) of phosphatidylinositol-3-kinase (PI3K) p110δ or conditional knockout of PI3K in Treg cells in mice effectively augmented anti-tumor immune responses without incurring autoimmunity in the mutant mice [79]. Although these findings need to be confirmed in humans, these studies suggest that TCR-proximal signaling molecules can be good targets for developing small molecule compounds to achieve selective depletion of tumor-infiltrating effector Treg cells.…”

Improving T-cell expansion and function for adoptive T-cell therapy using ex vivo treatment with PI3Kδ inhibitors and VIP antagonists

“…36 PI3Kd signaling has been shown to be crucial for CD8 Tcell-mediated antilisteria responses and also in the function of regulatory T cells in murine solid tumor models. 37,38 However, the differentiation signals downstream of PI3Kd, including AKT, make it an attractive target to modulate during anti-CD3/CD28 bead stimulation, as strong TCR stimulation leads to exhaustion and terminal differentiation of T cells. 39 Naive and central memory T cells are the most effective in T-cell-based therapies, and partially blocking terminal differentiation during CD3/C28 bead-mediated expansion is thus an attractive strategy to improve the quality of T cells used for adoptive cancer therapy.…”

Small Molecules Drive Big Improvements in Immuno‐Oncology Therapies

“…Inhibition of PI3Kδ in T‐reg cells leads to enhanced cytotoxic T‐cell function and restricts tumor growth 21. Currently, idelalisib is being evaluated in combination with pembrolizumab in indications where idelalisib is already approved, including CLL and B‐cell lymphomas 22…”