背景:嗜铬细胞增多症引起大量,成簇基因组重排在癌症中很普遍,被认为是肿瘤发生和进展的新范例.在这项研究中,我们调查了染色体之间的关联,抗肿瘤免疫反应,和对免疫检查点阻断(ICB)的反应性。方法:在发现集(n=9403)和验证集(n=1140)中进行免疫细胞浸润的定量和免疫相关信号通路的功能富集。我们研究了嗜铬细胞和抗肿瘤免疫反应之间的关联。在免疫治疗队列中,我们引入了基于拷贝数改变的染色体异常评分(CPSs)来评估染色体异常的程度,以评估其与ICB反应性的相关性.结果:在发现集和验证集中,CD8+T细胞与Tregs的比例,TAM,和MDSCs在有染色体增生的肿瘤中明显降低(分别为P=1.5×10-13,P=5.4×10-8和P=1.2×10-4,TCGA;P=1.0×10-13,P=3.6×10-15,P=3.3×10-3,PCAWG)。抗肿瘤免疫作用的相关通路在无色素沉着的肿瘤中显著富集。嗜铬细胞增多症可以作为一个独立的预测因子,低CPS患者在免疫治疗后经历了更长的总生存期(OS)[HR,1.90;95%置信区间,1.10-3.28;P=0.019]。结论:我们的发现强调了在具有色素沉着的肿瘤中减少的细胞毒性免疫浸润和在肿瘤微环境中增强的免疫抑制。因此,嗜铬细胞增多症可以作为一种潜在的指标来帮助识别对ICB有反应的患者。可以补充已建立的生物标志物。
Background:
Chromothripsis caused massive, clustered genomic rearrangements is prevalent in cancer and is considered a new paradigm for tumorigenesis and progression. In this study, we investigated the association among
chromothripsis, anti-tumor immune responses, and responsiveness to immune checkpoint blockade (ICB). Methods: Quantification of immune cell infiltration and functional enrichment of immune-related signaling pathways were performed in the discovery set (n = 9403) and the validation set (n = 1140). we investigated the association between chromothripsis and anti-tumor immune responses. In the immunotherapy cohort, copy number alteration-based
chromothripsis scores (CPSs) were introduced to assess the extent of
chromothripsis to evaluate its association with responsiveness to ICB. Results: In the discovery set and the validation set, the ratios of CD8+ T cells to Tregs, TAMs, and MDSCs were significantly lower in tumors with chromothripsis (P = 1.5 × 10-13, P = 5.4 × 10-8, and P = 1.2 × 10-4, respectively, TCGA; P = 1.0 × 10-13, P = 3.6 × 10-15, and P = 3.3 × 10-3, respectively, PCAWG). The relevant pathways underlying the antitumor immune effect were significantly enriched in tumors without chromothripsis.
Chromothripsis can be used as an independent predictor, and patients with low-CPSs experienced longer overall survival (OS) after immunotherapy [HR, 1.90; 95% confidence interval, 1.10-3.28; P = 0.019]. Conclusions: Our findings highlight the reduced cytotoxic immune infiltration in tumors with chromothripsis and enhanced immunosuppression in the tumor microenvironment. Chromothripsis can thus be used as a potential indicator to help identify patients who will respond to ICB, which could complement established biomarkers.