Inhibiting macrophage PI3Kγ to enhance immunotherapy

Abstract

A recent paper published in Nature reports that the immunosuppressive activity of tumor-associated macrophages is regulated via PI3Kγ signaling. Small-molecule inhibitors targeting PI3Kγ stimulate T cell activity against tumor alone and add additional effects for clinically proven PD1 immunotherapy.

Figure 1

TAMs control the switch of immunostimulation and immunosuppression by PI3Kγ. Tumor cells secrete regulatory molecules to reprogram TAMs to a tumor-promoting phenotype. TAMs integrate these signals through PI3Kγ, which switches on the transcriptional activity of C/EBP while switching off that of NF-κB. Each of the transcription factors regulates a program that respectively inhibits or promotes the immunosurveilance by cytotoxic T lymphocytes (CTLs). Targeting PI3Kγ signaling by genetic ablation (scissors) or kinase inhibitors (KIs) tilt the balance of the immune microenvironment to enhance CTL activities and inhibit tumor growth and metastasis. Tumor cells, TAMs and other stromal cells can inhibit CTLs via the PD1 pathway. Simultaneous targeting of the two pathways has a further elevated effect on the treatment of cancer in mouse models.