美国哈佛大学医学院Judy Lieberman等研究人员合作发现，肿瘤编辑抑制先天性和适应性抗肿瘤免疫但可通过抑制DNA甲基化来逆转。相关论文于2024年8月21日在线发表在《自然—免疫学》杂志上。

研究人员利用单细胞RNA测序在乳腺癌基因工程小鼠模型（GEMM）中识别未经偏差的编辑基因。研究发现，晚期肿瘤抑制了抗肿瘤免疫基因，减少了浸润的免疫细胞和肿瘤-免疫细胞之间的通信。

先天免疫基因，尤其是干扰素刺激基因，在下调的肿瘤基因中占主导地位，而调节细胞内在恶性度的基因则大多未被编辑。在晚期肿瘤中，早期肿瘤中的初始和激活CD8⁺ T细胞被耗竭或前体耗竭细胞取代。

通过使用低剂量地西他滨抑制DNA甲基化，可以逆转免疫基因的抑制，这抑制了肿瘤生长并恢复了免疫控制，增加了肿瘤浸润淋巴细胞的数量、功能和记忆性，并减少了髓样抑制细胞的数量。地西他滨在GEMM模型及植入的乳腺和黑色素瘤肿瘤中诱导了重要的干扰素、焦亡和程序性坏死基因，从而引发了炎症性细胞死亡和免疫控制。

据了解，癌细胞通过基因编辑来逃避免疫监视。然而，目前缺乏关于早期肿瘤发生期间基因编辑的全基因组研究。

附：英文原文

Title: Tumor editing suppresses innate and adaptive antitumor immunity and is reversed by inhibiting DNA methylation

Author: Zhang, Ying, Naderi Yeganeh, Pourya, Zhang, Haiwei, Wang, Simon Yuan, Li, Zhouyihan, Gu, Bowen, Lee, Dian-Jang, Zhang, Zhibin, Ploumakis, Athanasios, Shi, Ming, Wu, Hao, Greer, Eric Lieberman, Hide, Winston, Lieberman, Judy

Issue&Volume: 2024-08-21

Abstract: Cancer cells edit gene expression to evade immunosurveillance. However, genome-wide studies of gene editing during early tumorigenesis are lacking. Here we used single-cell RNA sequencing in a breast cancer genetically engineered mouse model (GEMM) to identify edited genes without bias. Late tumors repressed antitumor immunity genes, reducing infiltrating immune cells and tumor–immune cell communications. Innate immune genes, especially interferon-stimulated genes, dominated the list of downregulated tumor genes, while genes that regulate cell-intrinsic malignancy were mostly unedited. Naive and activated CD8+ T cells in early tumors were replaced with exhausted or precursor-exhausted cells in late tumors. Repression of immune genes was reversed by inhibiting DNA methylation using low-dose decitabine, which suppressed tumor growth and restored immune control, increasing the number, functionality and memory of tumor-infiltrating lymphocytes and reducing the number of myeloid suppressor cells. Decitabine induced important interferon, pyroptosis and necroptosis genes, inflammatory cell death and immune control in GEMM and implanted breast and melanoma tumors.

DOI: 10.1038/s41590-024-01932-8

Source: https://www.nature.com/articles/s41590-024-01932-8