Department of Oncology, University of Oxford, Oxford, UK.
Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK.
Cancer Immunol Immunother. 2024 Aug 6;73(10):204. doi: 10.1007/s00262-024-03779-2.
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.
肿瘤微环境 (TME) 中免疫细胞和基质细胞的复杂相互作用显著影响肿瘤的进展。髓样细胞，包括肿瘤相关巨噬细胞 (TAMs)、中性粒细胞 (TANs) 和髓源性抑制细胞 (MDSCs)，有助于 TME 中的免疫抑制 (Nakamura 和 Smyth 在 Cell Mol Immunol 17(1):1-12 (2020)。https://doi.org/10.1038/s41423-019-0306-1;DeNardo 和 Ruffell 在 Nat Rev Immunol 19(6):369-382 (2019)。https://doi.org/10.1038/s41577-019-0127-6)。这对依赖宿主免疫发挥作用的新型免疫疗法提出了重大挑战。本系统评价探讨了抑制磷酸肌醇 3-激酶 γ (PI3Kγ) 作为逆转实体瘤中髓样细胞驱动的免疫抑制的策略的临床前证据。2022 年 10 月 6 日，使用关键词和主题词在 EMBASE、MEDLINE 和 PubMed 数据库中进行了检索，以捕获相关研究。这些研究侧重于动物模型中的 PI3Kγ 抑制，并经过了预先设定的纳入和排除标准。提取的数据包括肿瘤生长动力学、生存终点和免疫反应，对其进行了荟萃分析。遵循 PRISMA 和 MOOSE 指南。综述和荟萃分析共纳入了 36 项研究，涉及 73 个动物模型。肿瘤模型涵盖了乳腺癌、结直肠癌、肺癌、皮肤癌、胰腺癌、脑癌、肝癌、前列腺癌、头颈部癌、软组织癌、胃癌和口腔癌。研究中使用的主要 PI3Kγ 抑制剂是 IPI-549 和 TG100-115，对 γ 同工型具有较好的特异性。81%的研究探索了联合治疗，通常包括化疗、放疗、免疫检查点抑制剂、生物制剂或疫苗。对肿瘤生长动力学的分析显示，PI3Kγ 单药治疗的反应虽然具有统计学意义，但存在异质性，而联合治疗组的肿瘤生长则更一致地减少。生存分析显示，联合治疗显著增加了总体中位生存时间。本系统评价对 PI3Kγ 抑制在髓样细胞驱动的肿瘤免疫抑制中的临床前研究进行了全面分析。已确定的研究强调了 PI3Kγ 抑制在通过调节髓样细胞功能重塑肿瘤微环境方面的潜力。PI3Kγ 抑制与其他治疗方式的联合显示出增强的抗肿瘤作用，表明联合方法可能有助于克服免疫抑制。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，作为未来在不同实体瘤类型中进行临床探索的有希望的途径。
