Class I histone deacetylase inhibition promotes CD8 T cell activation in ovarian cancer.
Class I histone deacetylase inhibition promotes CD8 T cell activation in ovarian cancer.
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DOI：
10.1002/cam4.3337
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发表时间：
2021-01
期刊：
影响因子：
4
通讯作者：
Arend RC
中科院分区：
文献类型：
--
作者：
McCaw TR;Goel N;Brooke DJ;Katre AA;Londoño AI;Smith HJ;Randall TD;Arend RC
上皮性卵巢癌（EOC）患者通常表现为晚期疾病，对治疗构成重大挑战。虽然紫杉烷和铂类化疗加手术减积最初是有效的，但EOC的特点是耐药疾病的频繁复发。鉴于免疫细胞能够参与转移部位并阻止复发，免疫疗法代表了一种有吸引力的治疗模式;然而，卵巢癌中检查点阻断的应答率令人失望。在这里，我们测试了I类HDAC抑制是否可以促进自发和非自发EOC小鼠模型中的抗肿瘤T细胞应答。我们使用小鼠卵巢癌的自发性Tg‐ MISIR ‐Tag和非自发性ID 8模型来检验这一假设。使用nCounter PanCancer Mouse Immune Profiling Panel评估整个肿瘤转录变化。通过流式细胞术测量调节和效应T细胞的选择蛋白表达的变化。我们发现用I类HDAC抑制剂恩替司他治疗上调与CD 8 T细胞细胞毒性功能相关的通路和基因，同时下调髓源性抑制细胞化学引诱物。肿瘤和相关腹水中调节性T细胞的抑制能力显著降低，逆转了CD 8-Treg比率。我们的研究结果表明，I类HDAC抑制可以促进肿瘤内CD 8 T细胞的活化，这可能是通过损害EOC肿瘤微环境内的抑制网络实现的。以这种方式，I类HDAC抑制可能使晚期EOC对免疫治疗方式敏感。恩替司他处理后，对应于CD 8 T细胞活化和效应子功能的基因表达上调。I类HDAC抑制还损害上皮性卵巢癌中多个淋巴结的肿瘤内抑制网络。因此，I类HDAC抑制可以整合到当前的治疗策略中，以促进内源性抗肿瘤免疫应答并使卵巢癌对免疫疗法敏感。
Patients with epithelial ovarian cancer (EOC) typically present with late‐stage disease, posing a significant challenge to treatment. Although taxane and platinum‐based chemotherapy plus surgical debulking are initially effective, EOC is marked by frequent recurrence with resistant disease. Immunotherapy represents an appealing treatment paradigm given the ability of immune cells to engage metastatic sites and impede recurrence; however, response rates to checkpoint blockade in ovarian cancer have been disappointing. Here, we tested whether class I HDAC inhibition can promote anti‐tumor T cell responses in a spontaneous and nonspontaneous murine model of EOC. We used the spontaneous Tg‐MISIIR‐Tag and nonspontaneous ID8 models of murine ovarian cancer to test this hypothesis. Whole tumor transcriptional changes were assessed using the nCounter PanCancer Mouse Immune Profiling Panel. Changes in select protein expression of regulatory and effector T cells were measured by flow cytometry. We found that treatment with the class I HDAC inhibitor entinostat upregulated pathways and genes associated with CD8 T cell cytotoxic function, while downregulating myeloid derived suppressor cell chemoattractants. Suppressive capacity of regulatory T cells within tumors and associated ascites was significantly reduced, reversing the CD8‐Treg ratio. Our findings suggest class I HDAC inhibition can promote activation of intratumoral CD8 T cells, potentially by compromising suppressive networks within the EOC tumor microenvironment. In this manner, class I HDAC inhibition might render advanced‐stage EOC susceptible to immunotherapeutic treatment modalities. Expression of genes corresponding to CD8 T cell activation and effector function are upregulated following entinostat treatment. Class I HDAC inhibition also compromises the intratumoral suppressive network at multiple nodes in epithelial ovarian cancer. Accordingly, class I HDAC inhibition can be integrated into current treatment strategies to promote endogenous anti‐tumor immune responses and sensitize ovarian cancer to immunotherapy.
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影响因子：
3.4
作者：
Li, Jingjing;Liu, Ruihong;Fan, Yuhua
通讯作者：
Fan, Yuhua
影响因子：
4.7
作者：
Aghajanian C;Goff B;Nycum LR;Wang YV;Husain A;Blank SV
通讯作者：
Blank SV
影响因子：
17.1
作者：
Highfill SL;Cui Y;Giles AJ;Smith JP;Zhang H;Morse E;Kaplan RN;Mackall CL
通讯作者：
Mackall CL
影响因子：
6.7
作者：
Buggert M;Tauriainen J;Yamamoto T;Frederiksen J;Ivarsson MA;Michaëlsson J;Lund O;Hejdeman B;Jansson M;Sönnerborg A;Koup RA;Betts MR;Karlsson AC
通讯作者：
Karlsson AC
DOI：
10.1073/pnas.0509182102
发表时间：
2005-12-20
影响因子：
11.1
作者：
Sato, E;Olson, SH;Odunsi, K
通讯作者：
Odunsi, K