PI3Kγ is a molecular switch that controls immune suppression

PKB/Akt-dependent regulation of inflammation in cancer

“…Thus, targeting PI3K-PKB axis represents a promising strategy to enhance T cell mediated immune editing in tumors. Recent exciting studies with immune checkpoint blockers suggest a potential therapeutic combinatorial option with PI3K-PKB inhibitors, which might release the immune-suppressive role of TAMs [122]. Similar evidences have been obtained from the combination of checkpoint inhibitory molecules targeting T cells with CSF1R inhibitors targeting macrophage [123].…”

Small Molecules Drive Big Improvements in Immuno‐Oncology Therapies

“…IPI‐549 is being evaluated in a phase I clinical study, in which the combination of IPI‐549 with nivolumab is being investigated in a variety of cancer indications 26, 27…”

Inhibiting macrophage PI3Kγ to enhance immunotherapy

“…Thus, the overall therapeutic benefit of this precision targeting versus more global approaches is still an open question. This group's previous work also showed that PI3Kγ is required for recruitment of myeloid cells [7], but TAM number is unaltered in p110-deleted mice [4]. The reason for the apparent discrepancy is unclear, but it may involve compensation in the long term and/or local proliferation of tissue-resident macrophages, which have been recently shown to be able to self-maintain locally in the steady state [8].…”

“…However, the mechanism by which TAMs integrate external signals and translate them into a transcriptional program within the cells to modulate the immune response is unclear. In a recent study published in Nature, Kaneda et al [4] showed that PI3Kγ acts as a molecular switch turning on immunosuppression while shutting down immune-stimulatory activities. Using both genetic tools and pharmacological inhibitors of PI3Kγ, they showed that in macrophages the lack of PI3Kγ activity induced expression of MHCII and pro-inflammatory cytokines such as IL12 with a concomitant reduction in immunosuppressive molecules exemplified by IL10 and arginase.…”

“…Patients with a low PI3Kγ activity profile have a better survival for lung and head and neck cancers [4], suggesting that PI3Kγ inhibition holds promise in cancer treatment. A general question for drug development is the therapeutic window of the drug, i.e., the degree of maintaining therapeutic efficacy without inducing intolerable toxicity.…”