对调节癌症的人类功能变体进行大规模并行审讯 免疫监视 免疫监视
Ying Liu1,2, Yongshuo Liu1,3, Xuran Niu1
1Biomedical Pioneering Innovation Center, Beijing Advanced Innovation Center for Genomics, Peking-Tsinghua Center for Life Sciences, Peking University Genome Editing Research Center, State Key Laboratory of Gene Function and Modulation Research, School of Life Sciences, Peking University, Beijing, China.
Signal transduction and targeted therapy
|March 19, 2025
概括
这项研究确定了数千种影响PD-L1和HLA-I表达的新型癌症突变,这对免疫治疗反应至关重要. 一个特定的突变,SETD2_Y1666,增强了抗癌免疫反应和免疫疗法的有效性.
科学领域:
- 癌症免疫学 癌症免疫学
- 基因组学就是基因组学.
- 分子生物学分子生物学
背景情况:
- 针对PD-1/PD-L1的免疫检查点阻塞 (ICB) 疗法已经改变了癌症治疗.
- 瘤细胞表达PD-L1和HLA-I极大地影响了ICB的疗效.
- 影响这些调节者的体质突变与瘤进展和治疗反应有关,但缺乏全面的理解.
研究的目的:
- 系统地识别和描述调节PD-L1和HLA-I表达的癌症突变.
- 探索这些突变对癌症免疫监测和ICB反应的功能影响.
- 为指导临床诊断和开发新型癌症疗法提供资源.
主要方法:
- 利用 ABEmax 系统创建了一个大规模的 sgRNA 库 (约. 820,000 sgRNAs) 针对全基因组的氨酸,氨酸和氨酸残留物.
- 进行系统查以确定影响PD-L1或HLA-I表达的突变.
- 研究的功能机制包括对mRNA/蛋白质稳定性,DNA结合,蛋白质相互作用和酶活性的影响.
主要成果:
- 发现了成千上万种减少或增加PD-L1或HLA-I表达的新突变.
- 鉴定了影响酸化之外的多种细胞过程的突变,例如基因调节和蛋白质稳定性.
- 发现了同时调节PD-L1和HLA-I的突变,以SETD2_Y1666.6为例.
- 证明SETD2_Y1666在临床前模型中诱导了一致的表型效应,并提高了免疫疗法的疗效.
结论:
- 这项研究提供了功能残留物调节癌症免疫逃避的广泛目录.
- 这些发现为改善ICB治疗的临床诊断和患者分层提供了宝贵的见解.
- 鉴定的突变和机制为开发向癌症免疫疗法铺平了道路.
相关概念视频
02:21Cancers Originate from Somatic Mutations in a Single Cell
Cancer arises from mutations in the critical genes that allow healthy cells to escape cell cycle regulation and acquire the ability to proliferate indefinitely. Though originating from a single mutation event in one of the originator cells, cancer progresses when the mutant cell lines continue to gain more and more mutations, and finally, become malignant. For example, chronic myelogenous leukemia (CML) develops initially as a non-lethal increase in white blood cells, which progressively...
02:53Adaptive Mechanisms in Cancer Cells
Cancer cells accumulate genetic changes at an abnormally rapid rate due to the defects in the DNA repair mechanisms. From an evolutionary perspective, such genetic instability is advantageous for cancer development. Mutant cell lines accumulate a series of beneficial mutations that contribute to their progression into cancer.
Some of the advantages that cancer cells have on normal cells include - enhanced ability to divide without terminally differentiating, induce new blood vessel formation,...
Some of the advantages that cancer cells have on normal cells include - enhanced ability to divide without terminally differentiating, induce new blood vessel formation,...
01:05Cancer-Critical Genes II: Tumor Suppressor Genes
Genes usually encode proteins necessary for the proper functioning of a healthy cell. Mutations can often cause changes to the gene expression pattern, thereby altering the phenotype.
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
02:21Cancers Originate from Somatic Mutations in a Single Cell
Cancer arises from mutations in the critical genes that allow healthy cells to escape cell cycle regulation and acquire the ability to proliferate indefinitely. Though originating from a single mutation event in one of the originator cells, cancer progresses when the mutant cell lines continue to gain more and more mutations, and finally, become malignant. For example, chronic myelogenous leukemia (CML) develops initially as a non-lethal increase in white blood cells, which progressively...
02:53Adaptive Mechanisms in Cancer Cells
Cancer cells accumulate genetic changes at an abnormally rapid rate due to the defects in the DNA repair mechanisms. From an evolutionary perspective, such genetic instability is advantageous for cancer development. Mutant cell lines accumulate a series of beneficial mutations that contribute to their progression into cancer.
Some of the advantages that cancer cells have on normal cells include - enhanced ability to divide without terminally differentiating, induce new blood vessel formation,...
Some of the advantages that cancer cells have on normal cells include - enhanced ability to divide without terminally differentiating, induce new blood vessel formation,...
01:05Cancer-Critical Genes II: Tumor Suppressor Genes
Genes usually encode proteins necessary for the proper functioning of a healthy cell. Mutations can often cause changes to the gene expression pattern, thereby altering the phenotype.
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...