三阴性乳腺癌免疫治疗无效怎么办
三阴性乳腺癌与其他乳腺癌相比，攻击性较强，雌激素受体、孕激素受体、人类表皮生长因子受体HER2均为阴性，对内分泌治疗和HER2靶向治疗无效。2019年，中国学者根据基因组、转录组、临床特征，将三阴性乳腺癌分为四种亚型：雄激素受体管腔亚型、免疫调节亚型、基底样免疫抑制亚型、间充质样亚型，并且根据肿瘤免疫微环境特征，将三阴性乳腺癌进一步分为免疫炎症型、免疫沙漠型、免疫失活型。其中，免疫调节亚型或免疫炎症型对免疫治疗有效，非炎症型对免疫治疗无效。不过，三阴性乳腺癌非炎症型肿瘤免疫微环境的形成原因尚不明确。
2021年7月28日，《英国医学杂志》旗下《癌症免疫治疗杂志》在线发表复旦大学附属肿瘤医院邬思雨、肖毅、魏金丽、徐晓恩、金希、胡欣、李大强、江一舟、邵志敏等学者的研究报告，探索了三阴性乳腺癌非炎症型肿瘤免疫微环境的形成原因及其对策。
该研究利用复旦大学附属肿瘤医院三阴性乳腺癌多组学数据库的转录组和基因组数据，对驱动三阴性乳腺癌非炎症型肿瘤免疫微环境形成的关键基因组事件进行系统分析，通过体外和体内实验进一步揭示了免疫联合治疗的潜在机制和效果。
结果发现，三阴性乳腺癌经典的基底样亚型由两种不同的微环境表现型组成：炎症亚型和非炎症亚型。
进一步筛选证实，三阴性乳腺癌的原癌基因MYC扩增并过表达，可导致肿瘤免疫微环境的免疫浸润和细胞溶解活性较低。
根据机制分析，MYC与DNA甲基转移酶DNMT1启动子结合并激活三阴性乳腺癌细胞DNMT1转录，从而通过表观遗传调控方式抑制环状鸟苷酸腺苷酸合酶cGAS→干扰素基因刺激蛋白STING信号传导通路。
对于MYC过表达三阴性乳腺癌，DNMT1抑制剂地西他滨通过增强T淋巴细胞浸润，可将非炎症型肿瘤转变为炎症型肿瘤。
此外，地西他滨联合免疫细胞程序性死亡受体PD-1抑制剂，可逆转小鼠模型的T淋巴细胞耗竭并改善T淋巴细胞功能，对于MYC过表达三阴性乳腺癌可引发有效的抗肿瘤活性。
因此，该研究结果表明，经典的原癌基因MYC通过转录上调DNMT1，可抑制STING依赖性先天免疫，诱导三阴性乳腺癌免疫逃避。此外，DNMT1抑制剂地西他滨联合PD-1抑制剂免疫治疗对MYC过表达三阴性乳腺癌有效，故有必要进一步开展人体临床研究进行验证。
据悉，地西他滨已于2008年9月28日获批进入中国，中文商品名达珂，目前主要用于治疗骨髓增生异常综合征。
相关链接
中国对三阴性乳腺癌免疫分型施策
J Immunother Cancer. 2021 Jul 28;9(7):e002528.
MYC suppresses STING-dependent innate immunity by transcriptionally upregulating DNMT1 in triple-negative breast cancer.
Si-Yu Wu, Yi Xiao, Jin-Li Wei, Xiao-En Xu, Xi Jin, Xin Hu, Da-Qiang Li, Yi-Zhou Jiang, Zhi-Ming Shao.
Fudan University Shanghai Cancer Center, Shanghai, China; Shanghai Medical College, Fudan University, Shanghai, China.
BACKGROUND: Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer and lacks definite treatment targets. Tumor immune microenvironment (TIME) heterogeneity has a profound impact on the immunotherapy response. Tumors with non-inflamed TIME derive limited benefit from immunotherapy. However, what drives the formation of the non-inflamed TIME in TNBC remains unclear.
METHODS: Using our multiomics database of TNBC, we conducted an analysis to explore the key genomic events driving the formation of the non-inflamed TIME in TNBC. In vitro and in vivo studies further revealed potential mechanisms and the efficacy of combination treatment with immunotherapy.
RESULTS: With transcriptomic and genomic data, we systematically analyzed the TIME of TNBC and revealed that the classical basal-like subtype of TNBC consisted of two distinct microenvironment phenotypes, defined as the 'inflamed' and 'non-inflamed' subtypes. We performed further screening and demonstrated that MYC amplification and overexpression led to low immune infiltration and cytolytic activity in TIME. Mechanistically, MYC bound to DNMT1 promoter and activated DNMT1 transcription in TNBC cells, thus suppressing the Cyclic GMP-AMP synthase (cGAS)-STING pathway via an epigenetic regulatory way. In MYC-overexpressing TNBC, decitabine, an Food and Drug Administration (FDA)-approved DNA methyltransferase inhibitor, converted tumors from non-inflamed to inflamed tumors by enhancing T cell infiltration. Furthermore, the combination of decitabine with programmed cell death protein 1 (PD-1) inhibitor reversed T cell exhaustion and improved T cell function in mouse models, which elicited potent antitumor activity in MYC-overexpressing TNBC.
CONCLUSIONS: Our work elucidates that the classic oncogene MYC induces immune evasion by repressing innate immunity. Furthermore, we provide a rationale for combining DNA methyltransferase inhibition with immunotherapy for the treatment of MYC-overexpressing TNBC.
DOI: 10.1136/jitc-2021-002528