Martin Timothy D, Patel Rupesh S, Cook Danielle R, Choi Mei Yuk, Patil Ajinkya, Liang Anthony C, Li Mamie Z, Haigis Kevin M, Elledge Stephen J
Division of Genetics, Brigham and Women's Hospital, Howard Hughes Medical Institute, Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Science. 2021 Sep 17;373(6561):1327-1335. doi: 10.1126/science.abg5784. Epub 2021 Sep 16.
During tumorigenesis, tumors must evolve to evade the immune system and do so by disrupting the genes involved in antigen processing and presentation or up-regulating inhibitory immune checkpoint genes. We performed in vivo CRISPR screens in syngeneic mouse tumor models to examine requirements for tumorigenesis both with and without adaptive immune selective pressure. In each tumor type tested, we found a marked enrichment for the loss of tumor suppressor genes (TSGs) in the presence of an adaptive immune system relative to immunocompromised mice. Nearly one-third of TSGs showed preferential enrichment, often in a cancer- and tissue-specific manner. These results suggest that clonal selection of recurrent mutations found in cancer is driven largely by the tumor’s requirement to avoid the adaptive immune system.
在肿瘤发生过程中，肿瘤必须进化以逃避免疫系统，其方式是破坏参与抗原加工和呈递的基因，或上调抑制性免疫检查点基因。我们在同基因小鼠肿瘤模型中进行了体内CRISPR筛选，以研究在有和没有适应性免疫选择压力的情况下肿瘤发生的必要条件。在每种测试的肿瘤类型中，我们发现相对于免疫功能低下的小鼠，在存在适应性免疫系统的情况下，肿瘤抑制基因（TSGs）的缺失有明显富集。近三分之一的TSGs表现出优先富集，且通常以癌症和组织特异性的方式出现。这些结果表明，癌症中发现的复发性突变的克隆选择很大程度上是由肿瘤避免适应性免疫系统的需求驱动的。
