免疫系統(tǒng)既可促癌，也可抑癌,。多種器官的慢性炎癥狀態(tài)容易形成腫瘤,，表明免疫系統(tǒng)可以促進(jìn)腫瘤形成。相反,，由于腫瘤細(xì)胞與正常細(xì)胞的分子差異,，免疫系統(tǒng)可以靶向并殺死腫瘤細(xì)胞。在腫瘤形成期間,，為了避免被人體免疫系統(tǒng)殺死,，腫瘤必須不斷進(jìn)化，破壞抗原加工呈遞相關(guān)基因或上調(diào)抑制性免疫檢查點(diǎn)基因,。因此,，腫瘤形成受到腫瘤細(xì)胞內(nèi)在機(jī)制的幫助，要么利用促腫瘤形成的炎癥,，要么逃避抗腫瘤免疫反應(yīng),。不過，用于研究腫瘤的小鼠通常缺乏完整的免疫系統(tǒng),，才能將人類腫瘤植入小鼠體內(nèi),。相比之下，自然進(jìn)化的腫瘤必須抗衡功能完整的免疫系統(tǒng)及其對某些細(xì)胞的破壞,。

　　2021年9月17日,，全球自然科學(xué)三大期刊之一、美國科學(xué)促進(jìn)會《科學(xué)》正刊發(fā)表哈佛大學(xué)醫(yī)學(xué)院,、布萊根醫(yī)院和波士頓婦女醫(yī)院,、霍華德休斯醫(yī)學(xué)研究所,、達(dá)納法伯癌癥研究所的研究報告，利用基因編輯技術(shù)實(shí)現(xiàn)在完整的免疫微環(huán)境中對促進(jìn)腫瘤細(xì)胞生長的基因進(jìn)行功能鑒定,，對小鼠三陰性乳腺癌等腫瘤模型的7500個基因進(jìn)行大規(guī)模篩查,，篩選已在體外和體內(nèi)廣泛用于識別癌癥可靶向治療的依賴性，分析可以逃避免疫的分子改變,，對有無適應(yīng)性（又稱獲得性,、后天性）免疫選擇壓力下的腫瘤形成進(jìn)行了比較。

　　該研究對小鼠三陰性乳腺癌4T1等腫瘤模型進(jìn)行測試,，結(jié)果發(fā)現(xiàn)免疫系統(tǒng)完整,、免疫功能正常的野生型小鼠，與缺乏成熟免疫系統(tǒng),、免疫功能低下的缺陷型小鼠相比,，抑癌基因缺失反而顯著增加。抑癌基因發(fā)生突變后,，即使小鼠免疫系統(tǒng)完整,、免疫功能正常，腫瘤細(xì)胞仍然快速增長,。而在已經(jīng)形成的腫瘤里,，也能檢測出大量突變的抑癌基因，近三分之一的抑癌基因通常以腫瘤和組織特異性方式優(yōu)先富集,。這些抑癌基因突變后,，反而能夠幫助腫瘤逃避免疫系統(tǒng)的攻擊，說明免疫系統(tǒng)與腫瘤細(xì)胞之間發(fā)生著激烈的競爭,，而腫瘤細(xì)胞可利用一切機(jī)會增加自己的存活概率,，其中就包括利用抑癌基因的突變。這些突變的抑癌基因不僅促進(jìn)腫瘤細(xì)胞快速生長,，還可有助于逃避免疫系統(tǒng),。

　　因此，該研究結(jié)果表明,，發(fā)現(xiàn)于癌癥的抑癌基因突變克隆選擇主要由腫瘤逃避適應(yīng)性免疫系統(tǒng)引起,，免疫系統(tǒng)對形成腫瘤的細(xì)胞施加選擇性壓力，促進(jìn)那些失去抑癌基因表達(dá)或激活特定癌基因的細(xì)胞存活,，免疫系統(tǒng)對推動多種癌癥的腫瘤進(jìn)化發(fā)揮著重要作用,，突出了免疫系統(tǒng)如何影響腫瘤細(xì)胞的遺傳和表觀遺傳改變，有望帶來全新的癌癥預(yù)防和治療策略,。

　　對此,，霍普金斯大學(xué)醫(yī)學(xué)院發(fā)表同期評論：免疫系統(tǒng)對腫瘤的相反作用。

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