PDF(Pubmed)
Abstract：
The antigen processing machinery (APM) components needed for a tumor cell to present an antigen to a T cell are expressed at low levels in solid tumors, constituting an important mechanism of immune escape. More than most other solid tumors, head and neck squamous cell carcinoma (HNSCC) cells tend to have low APM expression, rendering them insensitive to immune checkpoint blockade and most other forms of immunotherapy. In HNSCC, this APM deficiency is largely driven by high levels of EGFR and SHP2, leading to low expression and activation of STAT1; however, recent studies suggest that p53, which is often mutated in HNSCCs, may also play a role. In the current study, we aimed to investigate the extent to which STAT1 and p53 individually regulate APM component expression in HNSCC cells. We found that in cells lacking functional p53, APM expression could still be induced by interferon-gamma or DNA-damaging chemotherapy (cisplatin) as long as STAT1 expression remained intact; when both transcription factors were knocked down, APM component expression was abolished. When we bypassed these deficient pathways by rescuing the expression of NLRC5, APM expression was also restored. These results suggest that dual loss of functional STAT1 and p53 may render HNSCC cells incapable of processing and presenting antigens, but rescue of downstream NLRC5 expression may be an attractive strategy for restoring sensitivity to T cell-based immunotherapy.
摘要：
肿瘤细胞向T细胞呈递抗原所需的抗原加工机制（APM）成分在实体瘤中以低水平表达，构成免疫逃逸的重要机制。比大多数其他实体瘤多，头颈部鳞状细胞癌（HNSCC）细胞往往具有低APM表达，使他们对免疫检查点阻断和大多数其他形式的免疫疗法不敏感。在HNSCC，这种APM缺乏主要是由高水平的EGFR和SHP2引起的，导致STAT1的低表达和激活；然而，最近的研究表明，经常在HNSCCs中突变的p53，也可以发挥作用。在目前的研究中,我们旨在研究STAT1和p53在HNSCC细胞中各自调节APM组分表达的程度。我们发现，在缺乏功能性p53的细胞中，只要STAT1表达保持完整，干扰素-γ或DNA损伤化疗（顺铂）仍然可以诱导APM表达；当两个转录因子被敲低时，APM组分表达被废除。当我们通过挽救NLRC5的表达绕过这些缺陷途径时，APM表达也恢复了。这些结果表明，功能性STAT1和p53的双重丧失可能使HNSCC细胞无法加工和呈递抗原，但拯救下游NLRC5表达可能是恢复T细胞免疫治疗敏感性的有吸引力的策略.
