背景：染色体断裂导致的大规模、聚集的基因组重组在癌症中非常普遍，并被认为是肿瘤发生和进展的一个新典范。在本研究中，我们调查了染色体断裂、抗肿瘤免疫反应和免疫检查点阻断(ICB)之间的关联。 方法：在发现组(n=9403)和验证组(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。我们调查了染色体断裂和抗肿瘤免疫反应之间的关联。在免疫疗法队列中，引入了基于拷贝数变化的染色体断裂得分(CPS)来评估染色体断裂的程度，以评估其与对ICB的反应性的关联。 结果：在发现组和验证组中，CD8+ T细胞与Tregs、TAMs和MDSCs的比例在具有染色体断裂的肿瘤中显著降低(P=1.5×10-13，P=5.4×10-8和P=1.2×10-4，分别为TCGA，P=1.0×10-13，P=3.6×10-15和P=3.3×10-3，分别为PCAWG)。与抗肿瘤免疫效应相关的信号通路在没有染色体断裂的肿瘤中显著富集。染色体断裂可以作为一种独立的预测因子，患者在免疫治疗后经历更长的总生存期(OS)(HR，1.90；95％置信区间，1.10-3.28；P=0.019)。 结论：我们的研究结果突出了具有染色体断裂的肿瘤中降低的细胞毒性免疫浸润和肿瘤微环境中增强的免疫抑制。染色体断裂可以作为一个潜在的指标，帮助识别将会对ICB产生反应的患者，这可以补充已有的生物标志物。©作者。

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.© The author(s).