Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Parker Institute for Cancer Immunotherapy, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Cell. 2019 Aug 8;178(4):933-948.e14. doi: 10.1016/j.cell.2019.07.019.
Interferon-gamma (IFNG) augments immune function yet promotes T cell exhaustion through PDL1. How these opposing effects are integrated to impact immune checkpoint blockade (ICB) is unclear. We show that while inhibiting tumor IFNG signaling decreases interferon-stimulated genes (ISGs) in cancer cells, it increases ISGs in immune cells by enhancing IFNG produced by exhausted T cells (T). In tumors with favorable antigenicity, these T mediate rejection. In tumors with neoantigen or MHC-I loss, T instead utilize IFNG to drive maturation of innate immune cells, including a PD1TRAIL ILC1 population. By disabling an inhibitory circuit impacting PD1 and TRAIL, blocking tumor IFNG signaling promotes innate immune killing. Thus, interferon signaling in cancer cells and immune cells oppose each other to establish a regulatory relationship that limits both adaptive and innate immune killing. In melanoma and lung cancer patients, perturbation of this relationship is associated with ICB response independent of tumor mutational burden.
干扰素-γ（IFNG）增强免疫功能，但通过 PD-L1 促进 T 细胞耗竭。这些相反的作用如何整合来影响免疫检查点阻断（ICB）尚不清楚。我们表明，虽然抑制肿瘤 IFNG 信号会降低癌细胞中的干扰素刺激基因（ISGs），但通过增强衰竭 T 细胞（T 细胞）产生的 IFNG，它会增加免疫细胞中的 ISGs。在具有良好抗原性的肿瘤中，这些 T 细胞介导排斥。在具有新抗原或 MHC-I 缺失的肿瘤中，T 细胞反而利用 IFNG 来驱动先天免疫细胞的成熟，包括 PD1TRAIL ILC1 群体。通过使影响 PD1 和 TRAIL 的抑制性回路失活，阻断肿瘤 IFNG 信号会促进先天免疫杀伤。因此，癌细胞和免疫细胞中的干扰素信号相互拮抗，建立一个调节关系，限制适应性和先天免疫杀伤。在黑色素瘤和肺癌患者中，这种关系的扰乱与肿瘤突变负担无关的 ICB 反应相关。
