Epigenetic and Transcriptional Control of the Epidermal Growth Factor Receptor Regulates the Tumor Immune Microenvironment in Pancreatic Cancer.
Epigenetic and Transcriptional Control of the Epidermal Growth Factor Receptor Regulates the Tumor Immune Microenvironment in Pancreatic Cancer.
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表皮生长因子受体调控胰腺癌肿瘤免疫微环境的表观遗传和转录调控
DOI：
10.1158/2159-8290.cd-20-0519
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发表时间：
2021-03
期刊：
影响因子：
28.2
通讯作者：
Stanger BZ
中科院分区：
文献类型：
--
作者：
Li J;Yuan S;Norgard RJ;Yan F;Sun YH;Kim IK;Merrell AJ;Sela Y;Jiang Y;Bhanu NV;Garcia BA;Vonderheide RH;Blanco A;Stanger BZ
虽然免疫疗法已经彻底改变了癌症治疗，但胰腺导管腺癌（PDA）患者很少对这些治疗有反应，这是由于肿瘤微环境（TME）中T细胞的浸润和活化较差。我们进行了体内CRISPR筛选，并将赖氨酸脱甲基酶3A（KDM 3A）鉴定为PDA中免疫治疗反应的有效表观遗传调节剂。KDM 3A通过Krueppel样因子5（KLF 5）和SMAD家族成员4（SMAD 4）调节表皮生长因子受体（EGFR）的表达。肿瘤细胞中KDM 3A、KLF 5、SMAD 4或EGFR的消融改变了免疫TME并使肿瘤对联合免疫疗法敏感，而用EGFR抑制剂厄洛替尼治疗已建立的肿瘤则促使肿瘤内T细胞呈剂量依赖性增加。这项研究定义了肿瘤细胞调节其免疫微环境的表观遗传-转录机制，并强调了EGFR抑制剂作为PDA免疫治疗增敏剂的潜力。
Although immunotherapy has revolutionized cancer care, patients with pancreatic ductal adenocarcinoma (PDA) rarely respond to these treatments, a failure that is attributed to poor infiltration and activation of T cells in the tumor microenvironment (TME). We performed an in vivo CRISPR screen and identified lysine demethylase 3A (KDM3A) as a potent epigenetic regulator of immunotherapy response in PDA. Mechanistically, KDM3A acts through Krueppel-like factor 5 (KLF5) and SMAD family member 4 (SMAD4) to regulate the expression of the epidermal growth factor receptor (EGFR). Ablation of KDM3A, KLF5, SMAD4, or EGFR in tumor cells altered the immune TME and sensitized tumors to combination immunotherapy, while treatment of established tumors with an EGFR inhibitor erlotinib prompted a dose-dependent increase in intratumoral T cells. This study defines an epigenetic-transcriptional mechanism by which tumor cells modulate their immune microenvironment and highlights the potential of EGFR inhibitors as immunotherapy sensitizers in PDA.