Cell-intrinsic, non-immunogenic, regulation of PD-L1 in head neck squamous cell carcinoma and its implication on radiosensitivity

尽管进行了根治性手术和辅助(化疗)放疗，头颈部癌患者的5年总存活率不超过50%-60%。突破性进展是发现了用于靶向治疗的检查点抑制剂(如抗CTLA-4或抗PD-1)。抗PD-1对头颈部局部区域晚期或转移性鳞状细胞癌也有疗效，但应答率不超过20%。越来越多的证据表明，免疫治疗和放射治疗之间存在协同免疫原性作用，从而提高了这两种疗法的疗效。目前尚不清楚是否也存在独立于免疫系统的细胞相互作用。目前的文献表明，PD-L1具有一个胞内结构域，它介导了癌细胞的增殖、迁移和转移以及治疗耐药的信号传导。本课题组的第一个数据证实了PD-L1在HNSCC中的这种内在信号转导。由于PD-L1激活了特定的信号通路，如PI3K/AKT或ERK1/2，已被证明介导辐射抗性，因此，内在PD-L1也调节辐射敏感性似乎是合理的。我们的前期数据显示，头颈部鳞状细胞癌细胞系具有不同程度的放射敏感性。在这些细胞系中，特定信号通路(如PI3K/AKT)的表达以及PD-L1的区室特异性表达已被认为与辐射抗性有关。相比之下，HNSCC患者化疗前的癌组织显示与放射敏感性相关的PD-L1的膜表达。我们想要研究PD-L1在头颈癌中的细胞内在功能，它的定位，它的相互作用伙伴，以及由此产生的信号是否影响抗PD-L1治疗或放射治疗的疗效。通过皮下注射HNSCCs建立免疫缺陷小鼠模型，直接阻断内源性PD-L1和阻断相互作用蛋白(抗PI3K、抗CDK4/6)的有效性应从总体生存、转移和放射疗效方面予以证实。

Despite radical surgery and adjuvant (chemo)irradiation, 5-year overall survival of head neck cancer patients is not more than 50-60%. A breakthrough was discovery of the checkpoint inhibitors (e.g. anti CTLA-4 oder anti PD-1) for targeted therapy. For anti PD-1 the efficacy has also been shown for loco-regional advanced or metastasized squamous cell carcinoma of the head and neck, however response rates count not more than 20%. There is increasing evidence for synergistic immunogenic effects between immunotherapy and radiotherapy, thereby enhancing the effectiveness of both therapies. It remains unclear if there also exist cellular interactions, independent from the immune system. Current literature shows that PD-L1 has an intracellular domain which mediates signaling for proliferation, migration and metastasis as well as for therapy resistance of cancer cells. First data of our group confirms this intrinsic signaling of PD-L1 in HNSCC. As PD-L1 activates specific signaling pathways like PI3K/AKT or ERK 1/2 which have been shown to mediate radioresistance it seems reasonable that intrinsic PD-L1 also modulates radiosensitivity. Our pre-data shows different degrees of radiosensitivity of head neck squamous cell carcinoma cell lines. In these cell lines expression of specific signaling pathways (e.g. PI3K/AKT) as well as compartment specific expression of PD-L1 have emerged to be associated with radioresistance. In contrast cancer tissue of HNSCC patients prior to definite (chemo)irradiation displays membrane expression of PD-L1 associated with radiosensitivity. We would like to investigate the cell-intrinsic function of PD-L1 in head neck cancer, its localization, its partners of interaction, and if the resulting signaling influences the efficacy of anti-PD-L1 therapy or radiotherapy. By use of an immunodeficient mouse model with subcutaneously injected HNSCCs, effectiveness of direct intrinsic PD-L1 blockade but also blockade of interacting proteins (anti-PI3K, anti CDK4/6) should be confirmed with regard to overall survival, metastasis and efficacy of irradiation.