Department of Tumour Biology, Graduate School of Medicine, Seoul National University, Seoul, South Korea; Medical Science Research Institute, Seoul National University Bundang Hospital, Seongnam, Seoul, South Korea.
Department of Radiation Oncology, Seoul National University Bundang Hospital, Seongnam, Seoul, South Korea.
Eur J Cancer. 2021 Nov;157:450-463. doi: 10.1016/j.ejca.2021.08.029. Epub 2021 Oct 1.
We hypothesised that the combined use of radiation therapy and a phosphoinositide 3-kinaseγδ inhibitor to reduce immune suppression would enhance the efficacy of an immune checkpoint inhibitor.
Murine breast cancer cells (4T1) were grown in both immune-competent and -deficient BALB/c mice, and tumours were irradiated by 3 fractions of 24 Gy. A PD-1 blockade and a phosphoinositide 3-kinase (PI3K)γδ inhibitor were then administered every other day for 2 weeks. The same experiments were performed in humanised patient-derived breast cancer xenograft model and its tumour was sequenced to identify immune-related pathways and profile infiltrated immune cells. Transcriptomic and clinical data were acquired from The Cancer Genome Atlas pan-cancer cohort, and the deconvolution algorithm was used to profile immune cell repertoire.
Using a PI3Kγδ inhibitor, radiation therapy (RT) and PD-1 blockade significantly delayed primary tumour growth, boosted the abscopal effect and improved animal survival. RT significantly increased CD8+cytotoxic T-cell fractions, immune-suppressive regulatory T cells (T), myeloid-derived suppressor cells and M2 tumour-associated macrophages (TAMs). However, the PI3Kγδ inhibitor significantly lowered the proportions of T, myeloid-derived suppressor cells and M2 TAMs, achieving dramatic gains in splenic, nodal, and tumour CD8+ T-cell populations after triple combination therapy. In a humanised patient-derived breast cancer xenograft model, triple combination therapy significantly delayed tumour growth and decreased immune-suppressive pathways. In The Cancer Genome Atlas cohort, high T/CD8+ T cell and M2/M1 TAM ratios were associated with poor overall patient survival.
These findings indicate PI3Kγ and PI3Kδ are clinically relevant targets in an immunosuppressive TME, and combining PI3Kγδ inhibitor, RT and PD-1 blockade may overcome the therapeutic resistance of immunologically cold tumours.
Combining PI3Kγδ inhibitor, RT, and PD-1 blockade may be a viable clinical approach, helping to overcome the therapeutic resistance of immunologically cold tumours such as breast cancer.
我们假设联合使用放射治疗和磷酸肌醇 3-激酶γδ 抑制剂来减少免疫抑制，将增强免疫检查点抑制剂的疗效。
在免疫功能正常和缺陷的 BALB/c 小鼠中培养小鼠乳腺癌细胞（4T1），并对肿瘤进行 3 次 24Gy 的放射治疗。然后，每隔一天给予 PD-1 阻断和磷酸肌醇 3-激酶（PI3K）γδ 抑制剂，共 2 周。在人源化患者来源的乳腺癌异种移植模型中进行了相同的实验，并对其肿瘤进行了测序，以鉴定免疫相关途径和浸润免疫细胞的特征。从癌症基因组图谱泛癌队列中获取转录组和临床数据，并使用去卷积算法对免疫细胞谱进行分析。
使用 PI3Kγδ 抑制剂、放射治疗（RT）和 PD-1 阻断显著延迟了原发性肿瘤的生长，增强了远隔效应，并提高了动物的存活率。RT 显著增加了 CD8+细胞毒性 T 细胞的比例，免疫抑制性调节性 T 细胞（T）、髓源性抑制细胞和 M2 肿瘤相关巨噬细胞（TAMs）。然而，PI3Kγδ 抑制剂显著降低了 T、髓源性抑制细胞和 M2 TAMs 的比例，在三重联合治疗后，脾脏、淋巴结和肿瘤 CD8+T 细胞群显著增加。在人源化患者来源的乳腺癌异种移植模型中，三重联合治疗显著延迟了肿瘤的生长并降低了免疫抑制途径。在癌症基因组图谱队列中，高 T/CD8+T 细胞和 M2/M1 TAM 比值与患者总体生存率差相关。
这些发现表明，PI3Kγ 和 PI3Kδ 是免疫抑制性 TME 中的临床相关靶点，联合使用 PI3Kγδ 抑制剂、RT 和 PD-1 阻断可能克服免疫冷肿瘤的治疗抵抗。
联合使用 PI3Kγδ 抑制剂、RT 和 PD-1 阻断可能是一种可行的临床方法，有助于克服免疫冷肿瘤（如乳腺癌）的治疗抵抗。
