Division of Cancer Immunology, Research Institute/Exploratory Oncology Research & Clinical Trial Center (EPOC), National Cancer Center, Tokyo/Chiba, Japan.
Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Osaka, Japan.
Sci Immunol. 2021 Nov 12;6(65):eabc6424. doi: 10.1126/sciimmunol.abc6424.
PD-1 blockade exerts antitumor effects by reinvigorating tumor antigen–specific CD8 T cells. Whereas neoantigens arising from gene alterations in cancer cells comprise critical tumor antigens in antitumor immunity, a subset of non–small cell lung cancers (NSCLCs) harboring substantial tumor mutation burden (TMB) lack CD8 T cells in the tumor microenvironment (TME), which results in resistance to PD-1 blockade therapy. To overcome this resistance, clarifying the mechanism(s) impairing antitumor immunity in highly mutated NSCLCs is an urgent issue. Here, we showed that activation of the WNT/β-catenin signaling pathway contributed to the development of a noninflamed TME in tumors with high TMB. NSCLCs that lacked immune cell infiltration into the TME despite high TMB preferentially up-regulated the WNT/β-catenin pathway. Immunologic assays revealed that those patients harbored neoantigen-specific CD8 T cells in the peripheral blood but not in the TME, suggesting impaired T cell infiltration into the TME due to the activation of WNT/β-catenin signaling. In our animal models, the accumulation of gene mutations in cancer cells increased CD8 T cell infiltration into the TME, thus slowing tumor growth. However, further accumulation of gene mutations blunted antitumor immunity by excluding CD8 T cells from tumors in a WNT/β-catenin signaling-dependent manner. Combined treatment with PD-1 blockade and WNT/β-catenin signaling inhibitors induced better antitumor immunity than either treatment alone. Thus, we propose a mechanism-oriented combination therapy whereby immune checkpoint inhibitors can be combined with drugs that target cell-intrinsic oncogenic signaling pathways involved in tumor immune escape.
PD-1 阻断通过重新激活肿瘤抗原特异性 CD8 T 细胞发挥抗肿瘤作用。虽然源自癌细胞基因改变的新抗原构成了抗肿瘤免疫中的关键肿瘤抗原，但一部分携带大量肿瘤突变负荷（TMB）的非小细胞肺癌（NSCLC）在肿瘤微环境（TME）中缺乏 CD8 T 细胞，这导致对 PD-1 阻断治疗产生耐药性。为了克服这种耐药性，阐明在高度突变的 NSCLC 中损害抗肿瘤免疫的机制是当务之急。在这里，我们表明 WNT/β-连环蛋白信号通路的激活导致 TMB 高的肿瘤中出现非炎症性 TME。尽管 TMB 高，但缺乏免疫细胞浸润到 TME 的 NSCLC 更倾向于上调 WNT/β-连环蛋白通路。免疫测定显示，这些患者在外周血中存在新抗原特异性 CD8 T 细胞，但在 TME 中不存在，这表明由于 WNT/β-连环蛋白信号的激活，T 细胞浸润到 TME 受到损害。在我们的动物模型中，癌细胞中基因突变的积累增加了 CD8 T 细胞浸润到 TME 的程度，从而减缓了肿瘤的生长。然而，进一步积累的基因突变通过 WNT/β-连环蛋白信号依赖性方式将 CD8 T 细胞排除在肿瘤之外，从而削弱了抗肿瘤免疫。与单独使用任何一种药物相比，PD-1 阻断和 WNT/β-连环蛋白信号抑制剂的联合治疗诱导了更好的抗肿瘤免疫。因此，我们提出了一种基于机制的联合治疗方法，其中免疫检查点抑制剂可以与靶向参与肿瘤免疫逃逸的细胞内致癌信号通路的药物联合使用。
