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Chromothripsis is correlated with reduced cytotoxic immune infiltration and diminished responsiveness to checkpoint blockade immunotherapy

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 checkp...

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Detalles Bibliográficos
Autores principales: Chu, Han, Jin, Zheng, Cheng, Jia-nan, Jia, Qingzhu, Zhu, Bo, Cai, Haoyang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Ivyspring International Publisher 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10008737/
https://www.ncbi.nlm.nih.gov/pubmed/36923532
http://dx.doi.org/10.7150/thno.81350
Descripción
Sumario: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.