免疫系统为何杀不死三阴性乳腺癌

　　免疫系统既可促癌，也可抑癌。多种器官的慢性炎症状态容易形成肿瘤，表明免疫系统可以促进肿瘤形成。相反，由于肿瘤细胞与正常细胞的分子差异，免疫系统可以靶向并杀死肿瘤细胞。在肿瘤形成期间，为了避免被人体免疫系统杀死，肿瘤必须不断进化，破坏抗原加工呈递相关基因或上调抑制性免疫检查点基因。因此，肿瘤形成受到肿瘤细胞内在机制的帮助，要么利用促肿瘤形成的炎症，要么逃避抗肿瘤免疫反应。不过，用于研究肿瘤的小鼠通常缺乏完整的免疫系统，才能将人类肿瘤植入小鼠体内。相比之下，自然进化的肿瘤必须抗衡功能完整的免疫系统及其对某些细胞的破坏。

　　2021年9月17日，全球自然科学三大期刊之一、美国科学促进会《科学》正刊发表哈佛大学医学院、布莱根医院和波士顿妇女医院、霍华德休斯医学研究所、达纳法伯癌症研究所的研究报告，利用基因编辑技术实现在完整的免疫微环境中对促进肿瘤细胞生长的基因进行功能鉴定，对小鼠三阴性乳腺癌等肿瘤模型的7500个基因进行大规模筛查，筛选已在体外和体内广泛用于识别癌症可靶向治疗的依赖性，分析可以逃避免疫的分子改变，对有无适应性（又称获得性、后天性）免疫选择压力下的肿瘤形成进行了比较。

　　该研究对小鼠三阴性乳腺癌4T1等肿瘤模型进行测试，结果发现免疫系统完整、免疫功能正常的野生型小鼠，与缺乏成熟免疫系统、免疫功能低下的缺陷型小鼠相比，抑癌基因缺失反而显著增加。抑癌基因发生突变后，即使小鼠免疫系统完整、免疫功能正常，肿瘤细胞仍然快速增长。而在已经形成的肿瘤里，也能检测出大量突变的抑癌基因，近三分之一的抑癌基因通常以肿瘤和组织特异性方式优先富集。这些抑癌基因突变后，反而能够帮助肿瘤逃避免疫系统的攻击，说明免疫系统与肿瘤细胞之间发生着激烈的竞争，而肿瘤细胞可利用一切机会增加自己的存活概率，其中就包括利用抑癌基因的突变。这些突变的抑癌基因不仅促进肿瘤细胞快速生长，还可有助于逃避免疫系统。

　　因此，该研究结果表明，发现于癌症的抑癌基因突变克隆选择主要由肿瘤逃避适应性免疫系统引起，免疫系统对形成肿瘤的细胞施加选择性压力，促进那些失去抑癌基因表达或激活特定癌基因的细胞存活，免疫系统对推动多种癌症的肿瘤进化发挥着重要作用，突出了免疫系统如何影响肿瘤细胞的遗传和表观遗传改变，有望带来全新的癌症预防和治疗策略。

　　对此，霍普金斯大学医学院发表同期评论：免疫系统对肿瘤的相反作用。

Science. 2021 Sep 17;373(6561):1327-1335.

The adaptive immune system is a major driver of selection for tumor suppressor gene inactivation.

Timothy D. Martin, Rupesh S. Patel, Danielle R. Cook, Mei Yuk Choi, Ajinkya Patil, Anthony C. Liang, Mamie Z. Li, Kevin M. Haigis.

Brigham and Women's Hospital, Howard Hughes Medical Institute, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.

Defining tumor cell immune evasion: Mouse models used to study cancer often lack a full immune system, allowing implantation of human tumors into the mice. By contrast, naturally evolving tumors must contend with a fully functional immune system and its destruction of some of the cells (see the Perspective by Ho and Wood). Two groups now report studies on mouse models with a fully intact immune system. Martin et al. started with preexisting murine tumor cell lines and examined their continued evolution in vivo, whereas Del Poggetto et al. examined the development of new pancreatic tumors in the context of inflammation, as is often seen in human patients. In each study, the authors found that the immune system exerted a selective pressure on cells that would give rise to tumors, promoting the survival of those that had lost expression of tumor suppressor genes or activated a specific oncogene. The findings suggest a major role for the immune system in driving tumor evolution across multiple types of cancer.

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.

DOI: 10.1126/science.abg5784

Science. 2021 Sep 17;373(6561):1306-1307.

Opposing roles of the immune system in tumors.

Won Jin Ho, Laura D. Wood.

Johns Hopkins University School of Medicine, Baltimore, MD, USA.

The immune system can both promote and constrain cancer development. Chronic inflammatory conditions predispose to cancer formation in multiple organs, highlighting the role of the immune system in promoting tumorigenesis. Conversely, the immune system can target and kill neoplastic cells, owing to their molecular differences from normal cells. Therefore, tumor development is aided by processes intrinsic to cancer cells that either exploit protumorigenic inflammation or evade antitumor immune responses. On pages 1326 and 1327 of this issue, Del Poggetto et al. and Martin et al., respectively, demonstrate how cancer cells may co-opt these opposing effects of the immune system during tumor development. Together, these studies highlight how the immune system influences the genetic and epigenetic alterations in cancer cells, which may lead to improved strategies for cancer prevention and therapy.

DOI: 10.1126/science.abl5376