Wakita Daiko, Iwai Toshiki, Harada Suguru, Suzuki Miho, Yamamoto Kaname, Sugimoto Masamichi
Product Research Department, Kamakura Research Laboratories, Chugai Pharmaceutical Co., Ltd., Kanagawa, Japan.
Product Research Department, Kamakura Research Laboratories, Chugai Pharmaceutical Co., Ltd., Kanagawa, Japan
Anticancer Res. 2019 Apr;39(4):1749-1760. doi: 10.21873/anticanres.13281.
Immune checkpoint inhibitors have marked antitumor effect. However, monotherapy benefits only a limited population of patients, and further improvement of their effects is required. Here the therapeutic effect and immune response during anti-PD-L1 plus cisplatin combination therapy were investigated in a mouse model.
E.G7-OVA, expressing ovalbumin (OVA) gene as a model tumor antigen, was subcutaneously inoculated into syngeneic mice and treated with anti-PD-L1 with/without cisplatin. The tumor growth and activation status of immune cells were evaluated.
The anti-PD-L1 plus cisplatin combination resulted in a potent antitumor effect leading to tumor shrinkage compared to anti-PD-L1 or cisplatin alone, even though each alone, significantly inhibited tumor growth compared to the control group. During treatment, all groups, including that treated with cisplatin alone, had increased CD8 T-cell infiltration into tumor tissues compared with the control group, and the therapeutic effect was diminished by CD8 cell depletion. Aside from its direct cytotoxic effect, cisplatin alone increased chemokine levels and expression of immune checkpoint molecules on CD8 T-cells in the tumor site. The combination effectively activated OVA-specific CD8 T-cells. Furthermore, anti-PD-L1 alone and in combination with cisplatin, but not cisplatin alone, induced interferon-gamma-producing CD4 T-cells.
These findings provide a rationale for anti-PD-L1 plus cisplatin becoming a promising combination therapy for patients with cancer.
免疫检查点抑制剂具有显著的抗肿瘤作用。然而，单药治疗仅使有限的患者群体受益，需要进一步提高其疗效。在此，我们在小鼠模型中研究了抗PD-L1联合顺铂治疗期间的治疗效果和免疫反应。
将表达卵清蛋白（OVA）基因作为模型肿瘤抗原的E.G7-OVA皮下接种到同基因小鼠体内，并用抗PD-L1联合或不联合顺铂进行治疗。评估肿瘤生长和免疫细胞的激活状态。
与单独使用抗PD-L1或顺铂相比，抗PD-L1联合顺铂产生了强大的抗肿瘤作用，导致肿瘤缩小，尽管单独使用抗PD-L1或顺铂与对照组相比均显著抑制了肿瘤生长。在治疗期间，与对照组相比，所有组，包括单独使用顺铂治疗的组，肿瘤组织中CD8 T细胞浸润均增加，并且CD8细胞耗竭会减弱治疗效果。除了直接的细胞毒性作用外，单独使用顺铂还会增加肿瘤部位趋化因子水平以及CD8 T细胞上免疫检查点分子的表达。联合治疗有效地激活了OVA特异性CD8 T细胞。此外，单独使用抗PD-L1以及抗PD-L1与顺铂联合使用，但单独使用顺铂则不会，诱导产生了分泌干扰素-γ的CD4 T细胞。
这些发现为抗PD-L1联合顺铂成为一种有前景的癌症患者联合治疗方案提供了理论依据。
