Genome-scale CRISPR-Cas9 screening stratifies pancreatic cancer with distinct outcomes and immunotherapeutic efficacy

免疫疗法 清脆的 免疫系统 胰腺癌 肿瘤科 计算生物学 精密医学 生物 内科学 医学 癌症 免疫学 基因 遗传学
作者
Libo Wang,De Liang Fu,Siyuan Weng,Hui Xu,Long Liu,Chunguang Guo,Yuqing Ren,Xinwei Han,Xinwei Han
出处
期刊:Cellular Signalling [Elsevier BV]
卷期号:110: 110811-110811
标识
DOI:10.1016/j.cellsig.2023.110811
摘要

Pancreatic cancer (PC) was featured by dramatic heterogeneity and dismal outcomes. An ideal classification strategy capable of achieving risk stratification and individualized treatment is urgently needed to significantly improve prognosis. In this study, using the 105 prognostic cancer essential genes identified by genome-scale CRISPR-Cas9 screening and univariate Cox analysis, we established and verified three heterogeneous subtypes via non-negative matrix factorization (NMF) and nearest template prediction (NTP) algorithms in the TCGA-PAAD cohort (176 samples) and four multi-center cohorts (233 samples), respectively. Among them, C1 with the worst prognosis was enriched in immune-related pathways, possessed superior infiltration abundance of immune cells and immune checkpoint molecules expression, and might be most sensitive to immunotherapy. C3, owing a moderate prognosis, might be featured by proliferative biological function, and despite its highest immunogenicity, the defects in antigen processing and presentation ability coupled with barren immune environment render it ineffective for immunotherapy, while it had potential sensitivity to paclitaxel and methotrexate. Besides, C2 harbored the best prognosis and was characterized by metabolism-related functions. These results could deepen our understanding of PC molecular heterogeneity and provide a trustworthy reference for prognostic stratification management and precision medicine in clinical practice.
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