Targeting PI3K-gamma in myeloid driven tumour immune suppression: A Systematic Review and Meta-Analysis of the Preclinical Literature

The intricate interplay between immune and stromal cells within the tumour microenvironment (TME) significantly influences tumour progression. Myeloid cells, including tumour-associated macrophages (TAMs), neutrophils (TANs), and myeloid-derived suppressor cells (MDSCs), contribute to immune suppression in the TME 1,2. This poses a significant challenge for novel immunotherapeutics that rely on host immunity to exert their effect. This systematic review explores the preclinical evidence surrounding the inhibition of phosphoinositide 3-kinase gamma (PI3K{gamma}) as a strategy to reverse myeloid-driven immune suppression in solid tumours. EMBASE, MEDLINE, and PubMed databases were searched on 6th October 2022 using keyword and subject heading terms to capture relevant studies. The studies, focusing on PI3K{gamma} inhibition in animal models, were subjected to predefined inclusion and exclusion criteria. Extracted data included tumour growth kinetics, survival endpoints, and immunological responses which were meta-analysed. PRISMA and MOOSE guidelines were followed. A total of 36 studies covering 73 animal models were included in the review and meta-analysis. Tumour models covered breast, colorectal, lung, skin, pancreas, brain, liver, prostate, head and neck, soft tissue, gastric, and oral cancer. The predominant PI3K{gamma} inhibitors were IPI-549 and TG100-115, demonstrating favourable specificity for the gamma isoform. Combination therapies, often involving chemotherapy, radiotherapy, immune checkpoint inhibitors, biological agents, or vaccines, were explored in 81% of studies. Analysis of tumour growth kinetics revealed a statistically significant though heterogeneous response to PI3K{gamma} monotherapy, whereas the tumour growth in combination treated groups were more consistently reduced. Survival analysis showed a pronounced increase in median overall survival with combination therapy. This systematic review provides a comprehensive analysis of preclinical studies investigating PI3K{gamma} inhibition in myeloid-driven tumour immune suppression. The identified studies underscore the potential of PI3K{gamma} inhibition in reshaping the TME by modulating myeloid cell functions. The combination of PI3K{gamma} inhibition with other therapeutic modalities demonstrated enhanced antitumor effects, suggesting a synergistic approach to overcome immune suppression. These findings support the potential of PI3K{gamma}-targeted therapies, particularly in combination regimens, as a promising avenue for future clinical exploration in diverse solid tumour types. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=104 SRC="FIGDIR/small/593156v1_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@cb6915org.highwire.dtl.DTLVardef@5fe73corg.highwire.dtl.DTLVardef@462cf3org.highwire.dtl.DTLVardef@1313b00_HPS_FORMAT_FIGEXP M_FIG C_FIG