肿瘤微环境(TME)中免疫细胞和基质细胞之间的复杂相互作用显着影响肿瘤进展。髓系细胞,包括肿瘤相关巨噬细胞(TAMs),中性粒细胞(TAN),和骨髓来源的抑制细胞(MDSCs),有助于TME中的免疫抑制(Nakamura和SmythinCellMolImmunol17(1):1-12(2020)。https://doi.org/10.1038/s41423-019-0306-1;DeNardoandRuffellinNatRevImmunol19(6):369-382(2019).https://doi.org/10.1038/s41577-019-0127-6)。这对依赖宿主免疫发挥其作用的新型免疫治疗剂提出了重大挑战。本系统综述探讨了抑制磷酸肌醇3-激酶γ(PI3Kγ)作为逆转实体瘤中骨髓驱动的免疫抑制的策略的临床前证据。EMBASE,MEDLINE,和PubMed数据库于2022年10月6日使用关键词和主题标题检索,以获取相关研究.研究,关注动物模型中的PI3Kγ抑制,符合预定义的纳入和排除标准。提取的数据包括肿瘤生长动力学,生存终点,和免疫反应进行了荟萃分析。遵循PRISMA和MOOSE指南。综述和荟萃分析共纳入了涵盖73个动物模型的36项研究。覆盖乳房的肿瘤模型,结直肠,肺,皮肤,胰腺,大脑,肝脏,前列腺,头部和颈部,软组织,胃,口腔癌。主要的PI3Kγ抑制剂是IPI-549和TG100-115,证明了对γ同种型的有利特异性。联合疗法,通常涉及化疗,放射治疗,免疫检查点抑制剂,生物制剂,或者疫苗,在81%的研究中进行了探索。对肿瘤生长动力学的分析显示,尽管对PI3Kγ单一疗法的反应不均匀,但具有统计学意义。而联合治疗组的肿瘤生长更一致地减少。生存分析显示,联合治疗的中位总生存期明显增加。本系统综述提供了研究PI3Kγ抑制在骨髓驱动的肿瘤免疫抑制中的临床前研究的综合分析。确定的研究强调了PI3Kγ抑制在通过调节骨髓细胞功能重塑TME中的潜力。PI3Kγ抑制与其他治疗方式的组合显示出增强的抗肿瘤作用,提出了一种克服免疫抑制的协同方法。这些发现支持PI3Kγ靶向治疗的潜力,特别是在联合治疗方案中,作为未来不同实体瘤类型临床探索的有希望的途径。
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 (Nakamura and Smyth in Cell Mol Immunol 17(1):1-12 (2020). https://doi.org/10.1038/s41423-019-0306-1 ; DeNardo and Ruffell in Nat Rev Immunol 19(6):369-382 (2019). https://doi.org/10.1038/s41577-019-0127-6 ). 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 (PI3Kγ) as a strategy to reverse myeloid-driven immune suppression in solid tumours. EMBASE, MEDLINE, and PubMed databases were searched on 6 October 2022 using keyword and subject heading terms to capture relevant studies. The studies, focusing on PI3Kγ 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 PI3Kγ 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 PI3Kγ 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 PI3Kγ inhibition in myeloid-driven tumour immune suppression. The identified studies underscore the potential of PI3Kγ inhibition in reshaping the TME by modulating myeloid cell functions. The combination of PI3Kγ inhibition with other therapeutic modalities demonstrated enhanced antitumour effects, suggesting a synergistic approach to overcome immune suppression. These findings support the potential of PI3Kγ-targeted therapies, particularly in combination regimens, as a promising avenue for future clinical exploration in diverse solid tumour types.