Department of Radiation Oncology, Seoul National University, School of Medicine, Seoul, Republic of Korea; Medical Science Research Institute, Seoul National University Bundang Hospital, Seoul, Republic of Korea.
Medical Science Research Institute, Seoul National University Bundang Hospital, Seoul, Republic of Korea; Cancer Research Institute and Department of Tumor Biology, Graduate School of Medicine, Seoul National University, Seoul, Republic of Korea.
Int J Radiat Oncol Biol Phys. 2021 Jul 1;110(3):845-858. doi: 10.1016/j.ijrobp.2021.01.025. Epub 2021 Feb 26.
The poor response of breast cancer to immune checkpoint blockade might result from low immunogenicity and the immune-suppressive tumor microenvironment. We hypothesized that in situ tumor vaccination via radiation therapy (RT) and suppression of immune tolerance via phosphoinositide 3-kinase δ (PI3Kδ) inhibition would enhance the efficacy of immune checkpoint blockade.
4T1 murine breast cancer cells were grown in both immune-competent and -deficient BALB/c mice, and tumors were irradiated with 24 Gy in 3 fractions. A PD-1 blockade and a PI3Kαδ inhibitor were then administered every other day for 2 weeks. Fluorescence-activated cell sorting and immunohistochemistry served to monitor subsequent changes in immune cell repertoire.
The triple combination of RT, PD-1 blockade, and PI3Kαδ inhibitor significantly delayed tumor growth. The immune-deficient syngeneic 4T1 murine tumor model failed to show this tumor growth delay. Use of RT and PI3Kαδ inhibitor increased the proportions of CD8 T cells; PI3Kαδ inhibitor led to a decrease in regulatory T cells and polymorphonuclear myeloid-derived suppressor cells. The triple combination resulted in a remarkable increase in cytotoxic CD8 T cells, suggesting a prominent immune-modulatory effect. The abscopal effect was most prominent in the triple-combination therapy group, and it correlated with splenic CD8 T cell accumulation.
These findings collectively indicate that combining RT, PI3Kαδ inhibitor, and PD-1 blockade could be a viable approach, helping to overcome the therapeutic resistance of immunologically cold tumors, such as breast cancer, with an immunosuppressive tumor microenvironment.
乳腺癌对免疫检查点阻断的反应不佳可能源于低免疫原性和免疫抑制性肿瘤微环境。我们假设通过放射治疗（RT）进行原位肿瘤疫苗接种和通过磷酸肌醇 3-激酶 δ（PI3Kδ）抑制抑制免疫耐受，将增强免疫检查点阻断的疗效。
将 4T1 鼠乳腺癌细胞在免疫功能正常和缺陷的 BALB/c 小鼠中生长，并对肿瘤进行 24 Gy 的 3 次分割照射。然后每隔一天给予 PD-1 阻断和 PI3Kαδ 抑制剂，持续 2 周。荧光激活细胞分选和免疫组织化学用于监测随后免疫细胞谱系的变化。
RT、PD-1 阻断和 PI3Kαδ 抑制剂的三联组合显著延迟了肿瘤生长。免疫缺陷的同基因 4T1 鼠肿瘤模型未能显示出这种肿瘤生长延迟。使用 RT 和 PI3Kαδ 抑制剂增加了 CD8 T 细胞的比例；PI3Kαδ 抑制剂导致调节性 T 细胞和多形核髓样来源的抑制细胞减少。三联组合导致细胞毒性 CD8 T 细胞显著增加，表明具有明显的免疫调节作用。这种联合治疗的远隔效应最为明显，与脾 CD8 T 细胞的积累密切相关。
这些发现表明，将 RT、PI3Kαδ 抑制剂和 PD-1 阻断联合使用可能是一种可行的方法，有助于克服具有免疫抑制性肿瘤微环境的免疫冷肿瘤（如乳腺癌）的治疗抵抗。
