Targeting PI3K-gamma in myeloid driven tumour immune suppression: a systematic review and meta-analysis of the preclinical literature

The complex interactions between immune and stromal cells within the tumour microenvironment (TME) play a crucial role in driving tumour progression. Myeloid cells, including tumour-associated macrophages (TAMs), neutrophils (TANs), and myeloid-derived suppressor cells (MDSCs), are key contributors to immune suppression within the TME. This immune suppression presents a significant hurdle for new immunotherapies that depend on the host’s immune response. This systematic review investigates preclinical evidence on the inhibition of phosphoinositide 3-kinase gamma (PI3Kγ) as a strategy to counteract myeloid-driven immune suppression in solid tumours. A search of the EMBASE, MEDLINE, and PubMed databases was conducted on 6 October 2022 using relevant keywords and subject headings to identify pertinent studies. The selected studies, which focused on PI3Kγ inhibition in animal models, were evaluated according to predefined inclusion and exclusion criteria. Data extracted included tumour growth dynamics, survival outcomes, and immune responses, which were subsequently meta-analysed. The review followed PRISMA and MOOSE guidelines. A total of 36 studies encompassing 73 animal models were included in the review and meta-analysis. These models covered a range of cancers, including breast, colorectal, lung, skin, pancreas, brain, liver, prostate, head and neck, soft tissue, gastric, and oral cancers. The primary PI3Kγ inhibitors studied were IPI-549 and TG100-115, which showed high specificity for the gamma isoform. Combination therapies, often involving chemotherapy, radiotherapy, immune checkpoint inhibitors, biological agents, or vaccines, were examined in 81% of the studies. Analysis of tumour growth kinetics revealed a statistically significant but variable response to PI3Kγ monotherapy, while tumour growth in combination-treated groups was more consistently reduced. Survival analysis indicated a substantial increase in median overall survival with combination therapy. This systematic review provides a thorough analysis of preclinical studies on PI3Kγ inhibition in the context of myeloid-driven tumour immune suppression. The findings highlight the potential of PI3Kγ inhibition to reshape the TME by modulating myeloid cell activity. The combination of PI3Kγ inhibition with other therapeutic strategies demonstrated enhanced antitumour effects, suggesting a synergistic approach to overcoming immune suppression. These results support the potential of PI3Kγ-targeted therapies, particularly in combination regimens, as a promising avenue for future clinical research across various solid tumour types.